雷帕霉素对胶质瘤细胞糖代谢的影响及其抗肿瘤机制研究
|
摘要
目的：
胶质瘤是最常见的原发性脑部肿瘤,且多数切除后有复发可能。目前,针对恶性肿瘤细胞增殖、凋亡等方面的研究十分普遍。临床上使用的抗肿瘤药物大都是通过抑制肿瘤细胞的增殖、促进肿瘤细胞的凋亡来发挥作用的。PI3K/Akt/mTOR信号通路在多种恶性肿瘤中过度激活,调控恶性肿瘤的发生和发展。mTOR是PI3K/Akt信号通路下游重要的激酶,参与调控包括神经胶质瘤在内的多种肿瘤细胞的生存和增殖。雷帕霉素是mTOR的抑制剂,能通过抑制mTOR的活性,参与调控PI3K/Akt/mTOR信号通路在恶性肿瘤细胞中的作用。然而,关于雷帕霉素治疗神经胶质瘤的作用及相关分子机制尚未研究清楚。
在恶性肿瘤细胞中,糖酵解水平异常升高,多种糖酵解酶的表达和活性被过度激活,提示糖酵解途径可能为抗癌治疗提供丰富的靶点。最近有研究报道,microRNA-143受mTOR通路调控,且在多种恶性肿瘤中表达异常下调,其靶基因包括糖酵解关键限速酶己糖激酶2(HK2)。然而,关于mTOR通路、miRNA-143以及糖酵解途径在神经胶质瘤中的调控作用及三者之间的关系尚不清楚。
本研究利用人神经胶质瘤细胞系U251和CHG-5,探索雷帕霉素在增殖、凋亡、糖酵解等多个方面对神经胶质瘤的调控作用,并探讨相关的分子调控机制。
方法：
1)用100mM的雷帕霉素分别处理人胶质瘤U251和CHG-5细胞0、6、12、24h,MTT法检测U251和CHG-5细胞的增殖能力。
2)用100mM的雷帕霉素处理人胶质瘤U251和CHG-5细胞0、6、12、24h, FCM检测U251和CHG-5细胞凋亡水平的改变。
3)用100mM的雷帕霉素处理人胶质瘤U251和CHG-5细胞0、6、12、24h, Western Blotting检测磷酸化的S6激酶蛋白分子的表达水平。
4)用100mM的雷帕霉素分别处理人胶质瘤U251和CHG-5细胞0、6、12、24h,检测葡萄糖摄取和乳酸分泌的变化。
5)用100mM的雷帕霉素分别处理人胶质瘤U251和CHG-5细胞0、6、12、24h,分别检测己糖激酶、丙酮酸激酶和乳酸脱氢酶的活性。
6)用100mM的雷帕霉素分别处理人胶质瘤U251和CHG-5细胞0、6、12、24h, Western Blotting分别检测己糖激酶、丙酮酸激酶和乳酸脱氢酶的蛋白表达水平。
7)用100mM的雷帕霉素分别处理人神经胶质瘤U251和CHG-5细胞0、6、12、24h, Realtime qRT-PCR检测miR-143的表达变化。
结果：
1)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,细胞的增殖呈下降的趋势。
2)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,细胞凋亡呈上升的趋势。
3)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,S6K的磷酸化水平呈下降的趋势,提示mTOR活性受抑制。
4)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,细胞葡萄糖摄取和乳酸分泌量呈下降趋势。
5)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,糖酵解关键酶已糖激酶、丙酮酸激酶和乳酸脱氢酶的活性明显下调。
6)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,糖酵解关键酶已糖激酶(HK2)、丙酮酸激酶(PK)和乳酸脱氢酶(LDH)的蛋白表达明显下调。
7)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,miR-143的表达水平显著上调。
结论：
1)雷帕霉素通过抑制PI3K/Akt/mTOR信号通路的活性,抑制了神经胶质瘤细胞的增殖,同时诱导了细胞凋亡。
2)雷帕霉素通过抑制PI3K/Akt/mTOR信号通路的活性,进而抑制了神经胶质瘤细胞糖酵解水平,这可能是导致神经胶质瘤细胞的增殖变慢的重要原因。
3)雷帕霉素通过抑制PI3K/Akt/mTOR信号通路的活性,上调了miR-143的表达,进而下调了糖酵解限速酶HK2的表达,从而下调了神经胶质瘤细胞糖酵解水平。
Objective Glioma is the most common primary brain tumor, and may recur after the surgical removal of glioma. At present, the study of tumor cell proliferation and apoptosis is very common. In clinical, many widely used anticancer drugs are effective in treating tumors through inhibiting proliferation and inducing apoptosis of malignant tumor cells. PI3K/Akt/mTOR signaling pathway is frequently activated in a variety of tumors, and involves in tumor growth and development. MTOR, as a downstream molecule of the PI3K/Akt pathway, plays a central role in regulating the survival and proliferation of many malignant tumors cells including glioma. Rapamycin is an inhibitor of mTOR, and involves in the regulation of PI3K/Akt/mTOR signaling pathway in the malignant cells, via inhibiting mTOR activity. However, the anti-cancer effect of rapamycin on glioma as well as the involved molecular mechanism has not been thoroughly studied.
In various malignant tumor cells, glycolysis is commonly at a high level, mainly due to the abnormally elevated expression and activity of glycolytic enzymes, suggesting that the glycolytic pathway may provide sourceful targets for anti-cancer treatment. MicroRNA-143has been recently reported to be regulated by mTOR signal pathway, and its expression is abnormally reduced in a variety of malignant tumors, and its targets include glycolytic rate-limiting enzyme hexokinase2(HK2). However, the roles of mTOR pathway, miRNA-143, and glycolysis, as well as their relationship in the regulation of glioma remain unclear.
In this study, human glioma cell lines U251and CHG-5were used to explore the regulatory effects of rapamycin on proliferation, apoptosis, and glycolysis of glioma cells, and we also invesitgated the involved molecular mechanism.
Method
Rapamycin (100mM) was used to treat human glioma cell lines U251and CHG-5. MTT was performed to analyze the proliferation capacity of U251and CHG-5cells treated by100mM rapamycin with time. FCM was used to analyze the apoptosis levels of U251and CHG-5cells treated by100mM rapamycin with time. Western Blotting was used to examine the protein expression of p-S6K, on behalf of the activity of mTOR, in U251and CHG-5cells treated by100mM rapamycin with time. Glucose uptake and lactic acid secretion were assayed in U251and CHG-5cells treated by100mM rapamycin with time. The activity and protein expression levels of hexokinase2(HK2), pyruvate kinase (PK) and lactate dehydrogenase (LDH), all of which were key enzymes in glycolysis, were determined in U251and CHG-5cells treated by100mM rapamycin with time. The expression levels of miR-143, which directly negatively regulates HK2, were assayed in U251and CHG-5cells treated by100mM rapamycin with time.
Result
In U251and CHG-5cells treated by100mM rapamycin at0,6,12,24h, respectively, with the treatment time, the cell proliferation rate was gradually decreased, while the apoptosis levels showed an increasing trend. Western Blotting result showed that with the treatment time, the protein expression of p-S6k was gradually downregulated, indicating that the activity of mTOR was inhibited. Moreover, with the treatment time, glucose uptake and lactic acid secretion were decreased in U251and CHG-5cells, and the activity and protein expression levels of HK2, PK and LDH were all downregulated, suggesting that the glycolysis level was repressed. Furthermore, the miR-143expression level was gradually decreased with the treatment time of rapamycin in U251and CHG-5cells.
Conclusion
Rapamycin can inhibite cell proliferation and induce cell apoptosis in human glioma U251and CHG-5cells via downregulating the activity of PI3K/Akt/mTOR signaling pathway. Moreover, Rapamycin can also inhibiting the glycolysis in U251and CHG-5cells, which may contribute to the inhibition of cell proliferation. More importantly, rapamycin can upregulate the expression of miR-143through downregulate the acivity of PI3K/Akt/mTOR signaling, which can further inhibit the protein expression of the glycolysis rate-limiting enzyme HK2, the target of miR-143, and hence decrease the glycolysis level in U251and CHG-5cells.
胶质瘤是最常见的原发性脑部肿瘤,且多数切除后有复发可能。目前,针对恶性肿瘤细胞增殖、凋亡等方面的研究十分普遍。临床上使用的抗肿瘤药物大都是通过抑制肿瘤细胞的增殖、促进肿瘤细胞的凋亡来发挥作用的。PI3K/Akt/mTOR信号通路在多种恶性肿瘤中过度激活,调控恶性肿瘤的发生和发展。mTOR是PI3K/Akt信号通路下游重要的激酶,参与调控包括神经胶质瘤在内的多种肿瘤细胞的生存和增殖。雷帕霉素是mTOR的抑制剂,能通过抑制mTOR的活性,参与调控PI3K/Akt/mTOR信号通路在恶性肿瘤细胞中的作用。然而,关于雷帕霉素治疗神经胶质瘤的作用及相关分子机制尚未研究清楚。
在恶性肿瘤细胞中,糖酵解水平异常升高,多种糖酵解酶的表达和活性被过度激活,提示糖酵解途径可能为抗癌治疗提供丰富的靶点。最近有研究报道,microRNA-143受mTOR通路调控,且在多种恶性肿瘤中表达异常下调,其靶基因包括糖酵解关键限速酶己糖激酶2(HK2)。然而,关于mTOR通路、miRNA-143以及糖酵解途径在神经胶质瘤中的调控作用及三者之间的关系尚不清楚。
本研究利用人神经胶质瘤细胞系U251和CHG-5,探索雷帕霉素在增殖、凋亡、糖酵解等多个方面对神经胶质瘤的调控作用,并探讨相关的分子调控机制。
方法：
1)用100mM的雷帕霉素分别处理人胶质瘤U251和CHG-5细胞0、6、12、24h,MTT法检测U251和CHG-5细胞的增殖能力。
2)用100mM的雷帕霉素处理人胶质瘤U251和CHG-5细胞0、6、12、24h, FCM检测U251和CHG-5细胞凋亡水平的改变。
3)用100mM的雷帕霉素处理人胶质瘤U251和CHG-5细胞0、6、12、24h, Western Blotting检测磷酸化的S6激酶蛋白分子的表达水平。
4)用100mM的雷帕霉素分别处理人胶质瘤U251和CHG-5细胞0、6、12、24h,检测葡萄糖摄取和乳酸分泌的变化。
5)用100mM的雷帕霉素分别处理人胶质瘤U251和CHG-5细胞0、6、12、24h,分别检测己糖激酶、丙酮酸激酶和乳酸脱氢酶的活性。
6)用100mM的雷帕霉素分别处理人胶质瘤U251和CHG-5细胞0、6、12、24h, Western Blotting分别检测己糖激酶、丙酮酸激酶和乳酸脱氢酶的蛋白表达水平。
7)用100mM的雷帕霉素分别处理人神经胶质瘤U251和CHG-5细胞0、6、12、24h, Realtime qRT-PCR检测miR-143的表达变化。
结果：
1)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,细胞的增殖呈下降的趋势。
2)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,细胞凋亡呈上升的趋势。
3)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,S6K的磷酸化水平呈下降的趋势,提示mTOR活性受抑制。
4)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,细胞葡萄糖摄取和乳酸分泌量呈下降趋势。
5)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,糖酵解关键酶已糖激酶、丙酮酸激酶和乳酸脱氢酶的活性明显下调。
6)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,糖酵解关键酶已糖激酶(HK2)、丙酮酸激酶(PK)和乳酸脱氢酶(LDH)的蛋白表达明显下调。
7)用100mM的雷帕霉素分别处理神经胶质瘤U251和CHG-5细胞0、6、12、24h,随着处理时间的延长,miR-143的表达水平显著上调。
结论：
1)雷帕霉素通过抑制PI3K/Akt/mTOR信号通路的活性,抑制了神经胶质瘤细胞的增殖,同时诱导了细胞凋亡。
2)雷帕霉素通过抑制PI3K/Akt/mTOR信号通路的活性,进而抑制了神经胶质瘤细胞糖酵解水平,这可能是导致神经胶质瘤细胞的增殖变慢的重要原因。
3)雷帕霉素通过抑制PI3K/Akt/mTOR信号通路的活性,上调了miR-143的表达,进而下调了糖酵解限速酶HK2的表达,从而下调了神经胶质瘤细胞糖酵解水平。
Objective Glioma is the most common primary brain tumor, and may recur after the surgical removal of glioma. At present, the study of tumor cell proliferation and apoptosis is very common. In clinical, many widely used anticancer drugs are effective in treating tumors through inhibiting proliferation and inducing apoptosis of malignant tumor cells. PI3K/Akt/mTOR signaling pathway is frequently activated in a variety of tumors, and involves in tumor growth and development. MTOR, as a downstream molecule of the PI3K/Akt pathway, plays a central role in regulating the survival and proliferation of many malignant tumors cells including glioma. Rapamycin is an inhibitor of mTOR, and involves in the regulation of PI3K/Akt/mTOR signaling pathway in the malignant cells, via inhibiting mTOR activity. However, the anti-cancer effect of rapamycin on glioma as well as the involved molecular mechanism has not been thoroughly studied.
In various malignant tumor cells, glycolysis is commonly at a high level, mainly due to the abnormally elevated expression and activity of glycolytic enzymes, suggesting that the glycolytic pathway may provide sourceful targets for anti-cancer treatment. MicroRNA-143has been recently reported to be regulated by mTOR signal pathway, and its expression is abnormally reduced in a variety of malignant tumors, and its targets include glycolytic rate-limiting enzyme hexokinase2(HK2). However, the roles of mTOR pathway, miRNA-143, and glycolysis, as well as their relationship in the regulation of glioma remain unclear.
In this study, human glioma cell lines U251and CHG-5were used to explore the regulatory effects of rapamycin on proliferation, apoptosis, and glycolysis of glioma cells, and we also invesitgated the involved molecular mechanism.
Method
Rapamycin (100mM) was used to treat human glioma cell lines U251and CHG-5. MTT was performed to analyze the proliferation capacity of U251and CHG-5cells treated by100mM rapamycin with time. FCM was used to analyze the apoptosis levels of U251and CHG-5cells treated by100mM rapamycin with time. Western Blotting was used to examine the protein expression of p-S6K, on behalf of the activity of mTOR, in U251and CHG-5cells treated by100mM rapamycin with time. Glucose uptake and lactic acid secretion were assayed in U251and CHG-5cells treated by100mM rapamycin with time. The activity and protein expression levels of hexokinase2(HK2), pyruvate kinase (PK) and lactate dehydrogenase (LDH), all of which were key enzymes in glycolysis, were determined in U251and CHG-5cells treated by100mM rapamycin with time. The expression levels of miR-143, which directly negatively regulates HK2, were assayed in U251and CHG-5cells treated by100mM rapamycin with time.
Result
In U251and CHG-5cells treated by100mM rapamycin at0,6,12,24h, respectively, with the treatment time, the cell proliferation rate was gradually decreased, while the apoptosis levels showed an increasing trend. Western Blotting result showed that with the treatment time, the protein expression of p-S6k was gradually downregulated, indicating that the activity of mTOR was inhibited. Moreover, with the treatment time, glucose uptake and lactic acid secretion were decreased in U251and CHG-5cells, and the activity and protein expression levels of HK2, PK and LDH were all downregulated, suggesting that the glycolysis level was repressed. Furthermore, the miR-143expression level was gradually decreased with the treatment time of rapamycin in U251and CHG-5cells.
Conclusion
Rapamycin can inhibite cell proliferation and induce cell apoptosis in human glioma U251and CHG-5cells via downregulating the activity of PI3K/Akt/mTOR signaling pathway. Moreover, Rapamycin can also inhibiting the glycolysis in U251and CHG-5cells, which may contribute to the inhibition of cell proliferation. More importantly, rapamycin can upregulate the expression of miR-143through downregulate the acivity of PI3K/Akt/mTOR signaling, which can further inhibit the protein expression of the glycolysis rate-limiting enzyme HK2, the target of miR-143, and hence decrease the glycolysis level in U251and CHG-5cells.
引文
[1]Marumoto, T. and H. Saya. Molecular biology of glioma[J]. Adv Exp Med Biol,2012,746:2-11.
[2]Fan, Q.W. and W.A. Weiss. Inhibition of PI3K-Akt-mTOR signaling in glioblastoma by mTORCl/2 inhibitors[J]. Methods Mol Biol,2012,821:349-59.
[3]Sheppard, K., K.M. Kinross, B. Solomon, et al. Targeting PI3 kinase/AKT/mTOR signaling in cancer[J]. Crit Rev Oncog,2012,17(1):69-95.
[4]Populo, H., J.M. Lopes, and P. Soares. The mTOR Signalling Pathway in Human Cancer[J]. Int J Mol Sci,2012,13(2):1886-918.
[5]Wu, P. and Y.Z. Hu. PI3K/Akt/mTOR pathway inhibitors in cancer:a perspective on clinical progress[J]. Curr Med Chem,2010,17(35):4326-41.
[6]Ching, C.B. and D.E. Hansel. Expanding therapeutic targets in bladder cancer:the PI3K/Akt/mTOR pathway[J]. Lab Invest,2010,90(10):1406-14.
[7]Bjornsti, M.A. and P.J. Houghton. The TOR pathway:a target for cancer therapy[J]. Nat Rev Cancer,2004,4(5):335-48.
[8]Hay, N. and N. Sonenberg. Upstream and downstream of mTOR[J]. Genes Dev,2004,18(16):1926-45.
[9]Thomas, S.L., R. Alam, N. Lemke, et al. PTEN augments SPARC suppression of proliferation and inhibits SPARC-induced migration by suppressing SHC-RAF-ERK and AKT signaling[J]. Neuro Oncol,2010,12(9):941-55.
[10]Fan, Q.W. and W.A. Weiss. Isoform specific inhibitors of PI3 kinase in glioma[J]. Cell Cycle,2006,5(20):2301-5.
[11]Comprehensive genomic characterization defines human glioblastoma genes and core pathways[J]. Nature,2008,455(7216):1061-8.
[12]Liu, L., L. Gong, Y. Zhang, et al. Glycolysis in Panc-1 human pancreatic cancer cells is inhibited by everolimus[J]. Exp Ther Med,2013,5(1):338-342.
[13]Willems, L., N. Chapuis, A. Puissant, et al. The dual mTORCl and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia[J]. Leukemia,2012,26(6):1195-202.
[14]Pinto-Leite, R., R. Arantes-Rodrigues, C. Palmeira, et al. Everolimus enhances gemcitabine-induced cytotoxicity in bladder-cancer cell lines[J]. J Toxicol Environ Health A,2012,75(13-15):788-99.
[15]Grzybowska-Izydorczyk, O. and P. Smolewski. mTOR kinase inhibitors as a treatment strategy in hematological malignancies [J]. Future Med Chem,2012, 4(4):487-504.
[16]Fan, Q.W., C.K. Cheng, T.P. Nicolaides, et al. A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma[J]. Cancer Res,2007, 67(17):7960-5.
[17]Sehgal, S.N., H. Baker, and C. Vezina. Rapamycin (AY-22,989), a new antifungal antibiotic. Ⅱ. Fermentation, isolation and characterization[J]. J Antibiot (Tokyo),1975,28(10):727-32.
[18]Muthukkumar, S., T.M. Ramesh, and S. Bondada. Rapamycin, a potent immunosuppressive drug, causes programmed cell death in B lymphoma cells[J]. Transplantation,1995,60(3):264-70.
[19]Barbet, N.C., U. Schneider, S.B. Helliwell, et al. TOR controls translation initiation and early G1 progression in yeast[J]. Mol Biol Cell,1996,7(1): 25-42.
[20]Shapira, M., E. Kakiashvili, T. Rosenberg, et al. The mTOR inhibitor rapamycin down-regulates the expression of the ubiquitin ligase subunit Skp2 in breast cancer cells[J]. Breast Cancer Res,2006,8(4):R46.
[21]Warburg, O. On the origin of cancer cells[J]. Science,1956,123(3191): 309-14.
[22]Zhao, S., H. Liu, Y. Liu, et al. miR-143 inhibits glycolysis and depletes sternness of glioblastoma stem-like cells[J]. Cancer Lett,2013.
[23]Hamanaka, R.B. and N.S. Chandel. Targeting glucose metabolism for cancer therapy[J]. J Exp Med,2012,209(2):211-5.
[24]Elstrom, R.L., D.E. Bauer, M. Buzzai, et al. Akt stimulates aerobic glycolysis in cancer cells[J]. Cancer Res,2004,64(11):3892-9.
[25]Rathmell, J.C., C.J. Fox, D.R. Plas, et al. Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival[J]. Mol Cell Biol,2003,23(20):7315-28.
[26]Fang, R., T. Xiao, Z. Fang, et al. MicroRNA-143 (miR-143) regulates cancer glycolysis via targeting hexokinase 2 gene[J]. J Biol Chem,2012,287(27): 23227-35.
[27]Gregersen, L.H., A. Jacobsen, L.B. Frankel, et al. microRNA-143 down-regulates Hexokinase 2 in colon cancer cells[J]. BMC Cancer,2012,12(1):232.
[28]Boon, R.A. and K.C. Vickers. Intercellular transport of microRNAs[J]. Arterioscler Thromb Vasc Biol,2013,33(2):186-92.
[29]Zhang, H., X. Cai, Y. Wang, et al. microRNA-143, down-regulated in osteosarcoma, promotes apoptosis and suppresses tumorigenicity by targeting Bcl-2[J]. Oncol Rep,2010,24(5):1363-9.
[30]Wong, P., M. Iwasaki, T.C. Somervaille, et al. The miR-17-92 microRNA polycistron regulates MLL leukemia stem cell potential by modulating p21 expression[J]. Cancer Res,2010,70(9):3833-42.
[31]Trang, P., P.P. Medina, J.F. Wiggins, et al. Regression of murine lung tumors by the let-7 microRNA[J]. Oncogene,2010,29(11):1580-7.
[32]Garzon, R., G. Marcucci, and C.M. Croce. Targeting microRNAs in cancer:rationale, strategies and challenges[J]. Nat Rev Drug Discov,2010,9(10): 775-89.
[33]Nimmo, R.A. and F.J. Slack. An elegant miRror:microRNAs in stem cells, developmental timing and cancer[J]. Chromosoma,2009,118(4):405-18.
[34]Peschiaroli, A., A. Giacobbe, A. Formosa, et al. miR-143 regulates hexokinase 2 expression in cancer cells[J]. Oncogene,2012.
[35]Cheng, C.C., S.M. Yang, C.Y. Huang, et al. Molecular mechanisms of ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells[J]. Cancer Chemother Pharmacol,2005,55(6):531-40.
[36]Popovich, D.G. and D.D. Kitts. Structure-function relationship exists for ginsenosides in reducing cell proliferation and inducing apoptosis in the human leukemia (THP-1) cell line[J]. Arch Biochem Biophys,2002,406(1):1-8.
[37]Vivanco, I. and C.L. Sawyers. The phosphatidylinositol 3-Kinase AKT pathway in human cancer[J]. Nat Rev Cancer,2002,2(7):489-501.
[38]Zhao, J.J., H. Cheng, S. Jia, et al. The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation[J]. Proc Natl Acad Sci U S A,2006,103(44):16296-300.
[39]Fan, Q.W., Z.A. Knight, D.D. Goldenberg, et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma[J]. Cancer Cell,2006, 9(5):341-9.
[40]Parcellier, A., L.A. Tintignac, E. Zhuravleva, et al. PKB and the mitochondria:AKTing on apoptosis[J]. Cell Signal,2008,20(1):21-30.
[41]Neuhaus, P., J. Klupp, and J.M. Langrehr. mTOR inhibitors:an overview[J]. Liver Transpl,2001,7(6):473-84.
[42]Douros, J. and M. Suffness. New antitumor substances of natural origin[J]. Cancer Treat Rev,1981,8(1):63-87.
[43]Luan, F.L., R. Ding, V.K. Sharma, et al. Rapamycin is an effective inhibitor of human renal cancer metastasis[J]. Kidney Int,2003,63(3):917-26.
[44]Smolewski, P. Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway [J]. Anticancer Drugs,2006,17(5):487-94.
[45]Recher, C., O. Beyne-Rauzy, C. Demur, et al. Antileukemic activity of rapamycin in acute myeloid leukemia[J]. Blood,2005,105(6):2527-34.
[46]Geoerger, B., K. Kerr, C.B. Tang, et al. Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy[J]. Cancer Res,2001,61(4):1527-32.
[47]Wu, C., M. Wangpaichitr, L. Feun, et al. Overcoming cisplatin resistance by mTOR inhibitor in lung cancer[J]. Mol Cancer,2005,4(1):25.
[48]Avellino, R., S. Romano, R. Parasole, et al. Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells[J]. Blood,2005,106(4): 1400-6.
[49]Markman, B., R. Dienstmann, and J. Tabernero. Targeting the PI3K/Akt/mTOR pathway--beyond rapalogs[J]. Oncotarget,2010,1(7):530-43.
[50]Bartlett, J.M. Biomarkers and patient selection for PI3K/Akt/mTOR targeted therapies:current status and future directions[J]. Clin Breast Cancer,2010, 10 Suppl 3:S86-95.
[51]Hemmings, B.A. and D.F. Restuccia. PI3K-PKB/Akt pathway[J]. Cold Spring Harb Perspect Biol,2012,4(9):a011189.
[52]Fasolo, A. and C. Sessa. Targeting mTOR pathways in human malignancies[J]. Curr Pharm Des,2012,18(19):2766-77.
[53]Hartmann, C., G. Bartels, C. Gehlhaar, et al. PIK3CA mutations in glioblastoma multiforme[J]. Acta Neuropathol,2005,109(6):639-42.
[54]Samuels, Y., Z. Wang, A. Bardelli, et al. High frequency of mutations of the PIK3CA gene in human cancers[J]. Science,2004,304(5670):554.
[55]Manning, B.D. and L.C. Cantley. AKT/PKB signaling:navigating downstream[J]. Cell,2007,129(7):1261-74.
[56]Guertin, D.A. and D.M. Sabatini. The pharmacology of mTOR inhibition[J]. Sci Signal,2009,2(67):pe24.
[57]Alessi, D.R., S.R. James, C.P. Downes, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha[J]. Curr Biol,1997,7(4):261-9.
[58]Calleja, V., M. Laguerre, P.J. Parker, et al. Role of a novel PH-kinase domain interface in PKB/Akt regulation:structural mechanism for allosteric inhibition[J]. PLoS Biol,2009,7(1):e17.
[59]Calleja, V., D. Alcor, M. Laguerre, et al. Intramolecular and intermolecular interactions of protein kinase B define its activation in vivo[J]. PLoS Biol,2007,5(4):e95.
[60]Easton, J.B. and P.J. Houghton. mTOR and cancer therapy[J]. Oncogene, 2006,25(48):6436-46.
[61]Jia, S., Z. Liu, S. Zhang, et al. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis[J]. Nature,2008,454(7205):776-9.
[62]Ciraolo, E., M. Iezzi, R. Marone, et al. Phosphoinositide 3-kinase p110beta activity:key role in metabolism and mammary gland cancer but not development[J]. Sci Signal,2008,1(36):ra3.
[63]Faivre, S., G. Kroemer, and E. Raymond. Current development of mTOR inhibitors as anticancer agents[J]. Nat Rev Drug Discov,2006,5(8):671-88.
[64]Nakamura, J.L., E. Garcia, and R.O. Pieper. S6K1 plays a key role in glial transformation[J]. Cancer Res,2008,68(16):6516-23.
[65]Fan, Q.W., C. Cheng, Z.A. Knight, et al. EGFR signals to mTOR through PKC and independently of Akt in glioma[J]. Sci Signal,2009,2(55):ra4.
[66]Paez, J. and W.R. Sellers. PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling[J]. Cancer Treat Res,2003,115:145-67.
[67]Sui, L., J. Wang, and B.M. Li. Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex[J]. Learn Mem,2008,15(10):762-76.
[68]Blay, J.Y. Updating progress in sarcoma therapy with mTOR inhibitors[J]. Ann Oncol,2011,22(2):280-7.
[69]Shi, Y., J. Gera, L. Hu, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779[J]. Cancer Res,2002,62(17):5027-34.
[70]Gera, J.F., I.K. Mellinghoff, Y. Shi, et al. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin Dl and c-myc expression[J]. J Biol Chem,2004,279(4):2737-46.
[71]Bartel, D.P. MicroRNAs:genomics, biogenesis, mechanism, and function[J]. Cell,2004,116(2):281-97.
[72]Gambhir, S.S. Molecular imaging of cancer with positron emission tomography[J]. Nat Rev Cancer,2002,2(9):683-93.
[73]Frezza, C. and E. Gottlieb. Mitochondria in cancer:not just innocent bystanders[J]. Semin Cancer Biol,2009,19(1):4-11.
[74]Vander Heiden, M.G., L.C. Cantley, and C.B. Thompson. Understanding the Warburg effect:the metabolic requirements of cell proliferation[J]. Science,2009, 324(5930):1029-33.
[75]Pfeiffer, T., S. Schuster, and S. Bonhoeffer. Cooperation and competition in the evolution of ATP-producing pathways[J]. Science,2001,292(5516):504-7.
[76]Zu, X.L. and M. Guppy. Cancer metabolism:facts, fantasy, and fiction[J]. Biochem Biophys Res Commun,2004,313(3):459-65.
[77]Reitzer, L.J., B.M. Wice, and D. Kennell. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells[J]. J Biol Chem,1979, 254(8):2669-76.
[78]Lunt, S.Y. and M.G. Vander Heiden. Aerobic glycolysis:meeting the metabolic requirements of cell proliferation[J]. Annu Rev Cell Dev Biol,2011,27: 441-64.
[79]Treiber, T., N. Treiber, and G. Meister. Regulation of microRNA biogenesis and function[J]. Thromb Haemost,2012,107(4):605-10.
[80]Lewis, B.P., C.B. Burge, and D.P. Bartel. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets[J]. Cell,2005,120(1):15-20.
[81]Michael, M.Z., O.C. SM, N.G. van Holst Pellekaan, et al. Reduced accumulation of specific microRNAs in colorectal neoplasia[J]. Mol Cancer Res, 2003,1(12):882-91.
[82]Motoyama, K., H. Inoue, Y. Takatsuno, et al. Over-and under-expressed microRNAs in human colorectal cancer[J]. Int J Oncol,2009,34(4):1069-75.
[83]Slaby, O., M. Svoboda, P. Fabian, et al. Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer[J]. Oncology,2007,72(5-6):397-402.
[84]Wang, C.J., Z.G. Zhou, L. Wang, et al. Clinicopathological significance of microRNA-31,-143 and-145 expression in colorectal cancer[J]. Dis Markers,2009, 26(1):27-34.
[85]Kulda, V., M. Pesta, O. Topolcan, et al. Relevance of miR-21 and miR-143 expression in tissue samples of colorectal carcinoma and its liver metastases[J]. Cancer Genet Cytogenet,2010,200(2):154-60.
[86]Tokarz, P. and J. Blasiak. The role of microRNA in metastatic colorectal cancer and its significance in cancer prognosis and treatment[J]. Acta Biochim Pol, 2012,59(4):467-74.
[87]Lui, W.O., N. Pourmand, B.K. Patterson, et al. Patterns of known and novel small RNAs in human cervical cancer[J]. Cancer Res,2007,67(13):6031-43.
[88]Akao, Y., Y. Nakagawa, Y. Kitade, et al. Downregulation of microRNAs-143 and-145 in B-cell malignancies[J]. Cancer Sci,2007,98(12): 1914-20.
[89]Wang, X., S. Tang, S.Y. Le, et al. Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth[J]. PLoS One,2008,3(7):e2557.
[90]Amaral, F.C., N. Torres, F. Saggioro, et al. MicroRNAs differentially expressed in ACTH-secreting pituitary tumors[J]. J Clin Endocrinol Metab,2009, 94(1):320-3.
[91]Chen, H.C., G.H. Chen, Y.H. Chen, et al. MicroRNA deregulation and pathway alterations in nasopharyngeal carcinoma[J]. Br J Cancer,2009,100(6): 1002-11.
[92]Takagi, T., A. Iio, Y. Nakagawa, et al. Decreased expression of microRNA-143 and-145 in human gastric cancers[J]. Oncology,2009,77(1):12-21.
[93]Yu, T., X.Y. Wang, R.G. Gong, et al. The expression profile of microRNAs in a model of 7,12-dimethyl-benz[a]anthrance-induced oral carcinogenesis in Syrian hamster[J]. J Exp Clin Cancer Res,2009,28:64.
[94]Song, T., W. Xia, N. Shao, et al. Differential miRNA expression profiles in bladder urothelial carcinomas[J]. Asian Pac J Cancer Prev,2010,11(4):905-11.
[95]Han, Y., J. Chen, X. Zhao, et al. MicroRNA expression signatures of bladder cancer revealed by deep sequencing[J]. PLoS One,2011,6(3):e18286.
[96]Bockmeyer, C.L., M. Christgen, M. Muller, et al. MicroRNA profiles of healthy basal and luminal mammary epithelial cells are distinct and reflected in different breast cancer subtypes[J]. Breast Cancer Res Treat,2011,130(3):735-45.
[97]Wach, S., E. Nolte, J. Szczyrba, et al. MicroRNA profiles of prostate carcinoma detected by multiplatform microRNA screening[J]. Int J Cancer,2012, 130(3):611-21.
[98]Vosa, U., T. Vooder, R. Kolde, et al. Meta-analysis of microRNA expression in lung cancer[J]. Int J Cancer,2012.
[99]Pignot, G., G. Cizeron-Clairac, S. Vacher, et al. microRNA expression profile in a large series of bladder tumors:Identification of a 3-miRNA signature associated with aggressiveness of muscle-invasive bladder cancer[J]. Int J Cancer, 2013,132(11):2479-91.
[100]Salomon, D.S., R. Brandt, F. Ciardiello, et al. Epidermal growth factor-related peptides and their receptors in human malignancies[J]. Crit Rev Oncol Hematol,1995,19(3):183-232.
[101]Klos, K.S., S.L. Wyszomierski, M. Sun, et al. ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells[J]. Cancer Res,2006,66(4):2028-37.
[102]Zhao, Y. and Y. Sun. Targeting the mTOR-DEPTOR pathway by CRL E3 ubiquitin ligases:therapeutic application[J]. Neoplasia,2012,14(5):360-7.
[103]Papadimitrakopoulou, V. Development of PI3K/AKT/mTOR pathway inhibitors and their application in personalized therapy for non-small-cell lung cancer[J]. J Thorac Oncol,2012,7(8):1315-26.
[104]Fine, B., C. Hodakoski, S. Koujak, et al. Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a[J]. Science,2009, 325(5945):1261-5.
[105]Soria, J.C., F.A. Shepherd, J.Y. Douillard, et al. Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors[J]. Ann Oncol,2009,20(10): 1674-81.
[106]Shaw, R.J. and L.C. Cantley. Ras, PI(3)K and mTOR signalling controls tumour cell growth[J]. Nature,2006,441(7092):424-30.
[107]Zhao, L. and P.K. Vogt. Class I PI3K in oncogenic cellular transformation[J]. Oncogene,2008,27(41):5486-96.
[108]Awada, A., F. Cardoso, C. Fontaine, et al. The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer:results of a phase I study with pharmacokinetics[J]. Eur J Cancer,2008,44(1): 84-91.
[109]Robey, R.B. and N. Hay. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt[J]. Oncogene,2006,25(34): 4683-96.
[110]Jae, H.J., J.W. Chung, H.S. Park, et al. The antitumor effect and hepatotoxicity of a hexokinase II inhibitor 3-bromopyruvate:in vivo investigation of intraarterial administration in a rabbit VX2 hepatoma model [J]. Korean J Radiol,2009, 10(6):596-603.
[111]Christofk, H.R., M.G. Vander Heiden, M.H. Harris, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth[J]. Nature,2008,452(7184):230-3.
[112]Bluemlein, K., N.M. Gruning, R.G. Feichtinger, et al. No evidence for a shift in pyruvate kinase PKM1 to PKM2 expression during tumorigenesis[J]. Oncotarget,2011,2(5):393-400.
[113]Spoden, G.A., U. Rostek, S. Lechner, et al. Pyruvate kinase isoenzyme M2 is a glycolytic sensor differentially regulating cell proliferation, cell size and apoptotic cell death dependent on glucose supply [J]. Exp Cell Res,2009,315(16): 2765-74.
[114]Hitosugi, T., S. Kang, M.G. Vander Heiden, et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth[J]. Sci Signal,2009,2(97):ra73.
[115]Lv, L., D. Li, D. Zhao, et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth[J]. Mol Cell,2011,42(6):719-30.
[116]Vander Heiden, M.G., J.W. Locasale, K.D. Swanson, et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells[J]. Science,'2010, 329(5998):1492-9.
[117]Anastasiou, D., G. Poulogiannis, J.M. Asara, et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses [J]. Science,2011,334(6060):1278-83.
[118]Goldberg, M.S. and P.A. Sharp. Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression[J]. J Exp Med,2012,209(2):217-24.
[119]Luo, W., H. Hu, R. Chang, et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1[J]. Cell,2011,145(5): 732-44.
[120]Lee, J., H.K. Kim, Y.M. Han, et al. Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription[J]. Int J Biochem Cell Biol,2008,40(5):1043-54.
[121]Yang, W., Y. Xia, H. Ji, et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation[J]. Nature,2011,480(7375):118-22.
[122]Shim, H., C. Dolde, B.C. Lewis, et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth[J]. Proc Natl Acad Sci U S A,1997, 94(13):6658-63.
[123]Locasale, J.W. and L.C. Cantley. Metabolic flux and the regulation of mammalian cell growth[J]. Cell Metab,2011,14(4):443-51.
[124]Le, A., C.R. Cooper, A.M. Gouw, et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression[J]. Proc Natl Acad Sci USA,2010,107(5):2037-42.
[125]Younes, M., L.V. Lechago, J.R. Somoano, et al. Wide expression of the human erythrocyte glucose transporter Glut1 in human cancers[J]. Cancer Res,1996, 56(5):1164-7.
[126]Chan, D.A., P.D. Sutphin, P. Nguyen, et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality[J]. Sci Transl Med,2011,3(94):94ra70.
[127]Locasale, J.W., A.R. Grassian, T. Melman, et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis[J]. Nat Genet, 2011,43(9):869-74.
[128]Possemato, R., K.M. Marks, Y.D. Shaul, et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer[J]. Nature,2011, 476(7360):346-50.
[129]Vora, S., J.P. Halper, and D.M. Knowles. Alterations in the activity and isozymic profile of human phosphofructokinase during malignant transformation in vivo and in vitro:transformation-and progression-linked discriminants of malignancy[J]. Cancer Res,1985,45(7):2993-3001.
[130]Colombo, S.L., M. Palacios-Callender, N. Frakich, et al. Anaphase-promoting complex/cyclosome-Cdh1 coordinates glycolysis and glutaminolysis with transition to S phase in human T lymphocytes [J]. Proc Natl Acad Sci USA,2010,107(44):18868-73.
[131]Yao, N., C.L. Lu, J.J. Zhao, et al. A network of miRNAs expressed in the ovary are regulated by FSH[J]. Front Biosci,2009,14:3239-45.
[132]Zhang, J., X. Ji, D. Zhou, et al. miR-143 is critical for the formation of primordial follicles in mice[J]. Front Biosci,2013,18:588-97.
[133]Ohlsson Teague, E.M., K.H. Van der Hoek, M.B. Van der Hoek, et al. MicroRNA-regulated pathways associated with endometriosis[J]. Mol Endocrinol, 2009,23(2):265-75.
[134]He, Z., J. Yu, C. Zhou, et al. MiR-143 is not essential for adipose development as revealed by in vivo antisense targeting[J]. Biotechnol Lett,2013, 35(4):499-507.
[135]Walden, T.B., J.A. Timmons, P. Keller, et al. Distinct expression of muscle-specific microRNAs (myomirs) in brown adipocytes[J]. J Cell Physiol,2009, 218(2):444-9.
[136]Esau, C., X. Kang, E. Peralta, et al. MicroRNA-143 regulates adipocyte differentiation[J]. J Biol Chem,2004,279(50):52361-5.
[137]Takanabe, R., K. Ono, Y. Abe, et al. Up-regulated expression of microRNA-143 in association with obesity in adipose tissue of mice fed high-fat diet[J]. Biochem Biophys Res Commun,2008,376(4):728-32.
[138]Merkerova, M., A. Vasikova, M. Belickova, et al. MicroRNA expression profiles in umbilical cord blood cell lineages[J]. Stem Cells Dev,2010,19(1):17-26.
[139]Donahue, R.E., P. Jin, A.C. Bonifacino, et al. Plerixafor (AMD3100) and granulocyte colony-stimulating factor (G-CSF) mobilize different CD34+cell populations based on global gene and microRNA expression signatures[J]. Blood, 2009,114(12):2530-41.
[140]Bruchova, H., M. Merkerova, and J.T. Prchal. Aberrant expression of microRNA in polycythemia vera[J]. Haematologica,2008,93(7):1009-16.
[141]Akao, Y., Y. Nakagawa, A. Iio, et al. Role of microRNA-143 in Fas-mediated apoptosis in human T-cell leukemia Jurkat cells[J]. Leuk Res,2009, 33(11):1530-8.
[142]Dostalova Merkerova, M., Z. Krejcik, H. Votavova, et al. Distinctive microRNA expression profiles in CD34+ bone marrow cells from patients with myelodysplastic syndrome[J]. Eur J Hum Genet,2011,19(3):313-9.
[143]Cordes, K.R., N.T. Sheehy, M.P. White, et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity[J]. Nature,2009,460(7256):705-10.
[144]Wang, X., G. Hu, and J. Zhou. Repression of versican expression by microRNA-143[J]. J Biol Chem,2010,285(30):23241-50.
[145]Rangrez, A.Y., Z.A. Massy, V. Metzinger-Le Meuth, et al. miR-143 and miR-145:molecular keys to switch the phenotype of vascular smooth muscle cells[J]. Circ Cardiovasc Genet,2011,4(2):197-205.
[146]Boettger, T., N. Beetz, S. Kostin, et al. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir 143/145 gene cluster[J]. J Clin Invest,2009,119(9):2634-47.
[147]Palmieri, A., F. Pezzetti, A. Avantaggiato, et al. Titanium acts on osteoblast translational process[J]. J Oral Implantol,2008,34(4):190-5.
[148]Schmidt, W.M., A.O. Spiel, B. Jilma, et al. In vivo profile of the human leukocyte microRNA response to endotoxemia[J]. Biochem Biophys Res Commun, 2009,380(3):437-41.
[149]Nakagawa, Y., M. Iinuma, T. Naoe, et al. Characterized mechanism of alpha-mangostin-induced cell death:caspase-independent apoptosis with release of endonuclease-G from mitochondria and increased miR-143 expression in human colorectal cancer DLD-1 cells[J]. Bioorg Med Chem,2007,15(16):5620-8.
[150]Chen, X., X. Guo, H. Zhang, et al. Role of miR-143 targeting KRAS in colorectal tumorigenesis[J]. Oncogene,2009,28(10):1385-92.
[151]Xu, B., X. Niu, X. Zhang, et al. miR-143 decreases prostate cancer cells proliferation and migration and enhances their sensitivity to docetaxel through suppression of KRAS[J]. Mol Cell Biochem,2011,350(1-2):207-13.
[152]Ng, E.K., W.P. Tsang, S.S. Ng, et al. MicroRNA-143 targets DNA methyltransferases 3A in colorectal cancer[J]. Br J Cancer,2009,101(4):699-706.
[153]Noguchi, S., T. Mori, Y. Hoshino, et al. MicroRNA-143 functions as a tumor suppressor in human bladder cancer T24 cells[J]. Cancer Lett,2011,307(2): 211-20.
[154]Ni, Y., L. Meng, L. Wang, et al. MicroRNA-143 functions as a tumor suppressor in human esophageal squamous cell carcinoma[J]. Gene,2013,517(2): 197-204.
[155]Osaki, M., F. Takeshita, Y. Sugimoto, et al. MicroRNA-143 regulates human osteosarcoma metastasis by regulating matrix metalloprotease-13 expression[J]. Mol Ther,2011,19(6):1123-30.
[156]Hu, Y., Y. Ou, K. Wu, et al. miR-143 inhibits the metastasis of pancreatic cancer and an associated signaling pathway[J]. Tumour Biol,2012,33(6): 1863-70.
[157]Suzuki, H.I., K. Yamagata, K. Sugimoto, et al. Modulation of microRNA processing by p53[J]. Nature,2009,460(7254):529-33.
[158]Yamagata, T., J. Yoshizawa, S. Ohashi, et al. Expression patterns of microRNAs are altered in hypoxic human neuroblastoma cells[J]. Pediatr Surg Int, 2010,26(12):1179-84.
[159]Bradshaw-Pierce, E.L., T.M. Pitts, G. Kulikowski, et al. Utilization of quantitative in vivo pharmacology approaches to assess combination effects of everolimus and irinotecan in mouse xenograft models of colorectal cancer[J]. PLoS One,2013,8(3):e58089.
[1]Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ. Exciting new advances in neuro-oncology:the avenue to a cure for malignant glioma. CA Cancer J Clin 2010;60:166-93..
[2]Bjornsti M-A, Houghton PJ:The TOR pathway:a target for cancer therapy. Nat Rev Cancer 2004,4:335-348.
[3]Guertin DA, Sabatini DM:Defining the role of mTOR in cancer. Cancer Cell 2007,12:9-22.
[4]Hay N, Sonenberg N:Upstream and downstream of mTOR. Genes Dev 2004, 18:1926-1945.
[5]Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC:The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004,6:91-99.
[6]Grewe M, Gansauge F, Schmid RM, Adler G, Seufferlein T:Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells. Cancer Res 1999,59:3581-3587.
[7]Taha C, Liu Z, Jin J, Al-Hasani H, Sonenberg N, Klip A:Opposite translational control of GLUT1 and GLUT4 glucose transporter mRNAs in response to insulin. J Biol Chem 1999,274:33085-33091.
[8]Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet.2006;7:606-619
[9]Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer.2002;2:489-501.
[10]The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061-1068.
[11]Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science.2008;321:1807-1812.
[12]Huang HS, Nagane M, Klingbeil CK, et al. The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J Biol Chem.1997;272:2927-2935.
[13]Montgomery RB, Moscatello DK, Wong AJ, Cooper JA, Stahl WL. Differential modulation of mitogen-activated protein (MAP) kinase extracellular signal-related kinase kinase and MAP kinase activities by a mutant epidermal growth factor receptor. J Biol Chem.1995;270:30562-30566.
[14]Wikstrand CJ, McLendon RE, Friedman AH, Bigner DD. Cell surface localization and density of the tumor-associated variant of the epidermal growth factor receptor, EGFRvIII. Cancer Res.1997;57:4130-4140.
[15]Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest.2008; 118:3065-3074.
[16]Yoshimoto K, Dang J, Zhu S, et al. Development of a real-time RT-PCR assay for detecting EGFRvⅢ in glioblastoma samples. Clin Cancer Res. 2008;14:488-493.
[17]Huang PH, Mukasa A, Bonavia R, et al. Quantitative analysis of EGFRvⅢ cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma. Proc Natl Acad Sci USA.2007; 104:12867-12872.
[18]Ermoian RP, Furniss CS, Lamborn KR, et al. Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival. Clin Cancer Res.2002;8:1100-1106
[19]Holland EC. Gliomagenesis:genetic alterations and mouse models. Nat Rev Genet.2001;2:120-129.
[20]Sonoda Y, Ozawa T, Aldape KD, Deen DF, Berger MS, Pieper RO. Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. Cancer Res.2001;61:6674-6678.
[21]Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition. Sci Signal.2009;2:e24.
[22]Peterson TR, Laplante M, Thoreen CC, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell.2009;137:873-886.
[23]Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol.1997;7:261-269.
[24]Calleja V, Laguerre M, Parker PJ, Larijani B. Role of a novel PH-kinase domain interface in PKB/Akt regulation:structural mechanism for allosteric inhibition. PLoSBiol.2009;7:e17.
[25]Calleja V, Alcor D, Laguerre M, et al. Intramolecular and intermolecular interactions of protein kinase B define its activation in vivo. PLoS Biol.2007;5:e95.
[26]Easton JB, Houghton PJ. mTOR and cancer therapy. Oncogene.2006;25:6436-6446.
[27]Fan QW, Cheng C, Knight ZA, et al. EGFR signals to mTOR through PKC and independently of Akt in glioma. Sci Signal.2009;2:ra4.
[28]Nakamura JL, Garcia E, Pieper RO. S6K1 plays a key role in glial transformation.Cancer Res.2008;68:6516-6523.
[29]Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science.2005;307:1098-1101.
[30]Sabatini DM. mTOR and cancer:insights into a complex relationship.Nat Rev Cancer.2006;6:729-734.
[31]Zhang H, Bajraszewski N, Wu E, et al. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest. 2007; 117:730-738.
[32]Masri J, Bernath A, Martin J, et al. mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res.2007;67:11712-11720.
[33]Read RD, Cavenee WK, Furnari FB, Thomas JB. A drosophila model for EGFR-Ras and PI3K-dependent human glioma. PLoS Genet.2009;5:e1000374
[34]Faivre S, Kroemer G, Raymond E:Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006,5:671-688.
[35]Seghal SN, Baker H, Vezina C:Rapamycin (AY-22,989), a new antifungal antiobiotic II. Fermentation, isolation and characterization. J Antibiot [Tokyo] 1975,28:727-732.
[36]Douros J, Suffnes M:New antitumor substances of natural origin. Cancer Treat Rev 1981,8:63-87.
[37]Pascual J:Everolimus in clinical practice--renal transplantation. Nephrol Dial Transplant 2006,21(suppl 3):iii18-iii23.
[38]Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantinevon Kaeppler HA, Starling RC, S(?)rensen K, Hummel M, Lind JM, Abeywickrama KH, Bernhardt P, RAD B253 Study Group:Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003,349:847-858.
[39]Novartis Media Release. Certican approved by Swissmedic to reduce organ rejection risk in heart and kidney transplant patients 2005 [http://www.medicalnewstoday.com/articles/24886.php]. Accessed October 14,2009
[40]Hidalgo M, Buckner JC, Erlichman C, Pollack MS, Boni JP, Dukart G, Marshall B, Speicher L, Moore L, Rowinsky EK:A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 2006,12:5755-5763.
[41]TORISEL(?) (temsirolimus) prescribing information. Wyeth Pharmaceuticals Inc., Philadelphia, PA; 2008.
[42]Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, Patnaik A, Mathews L, Ricart AD, Mays T, Knowles H, Rivera VM, Kreisberg J, Bedrosian CL, Tolcher AW:Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 2008, 26:361-367.
[43]Fetterly GJ, Mita MM, Britten CD, Poplin E, Tap WD, Carmona A, Yonemoto L, Bedrosian CL, Rubin EH, Tolcher AW:Pharmacokinetics of oral deforolimus (AP23573, MK-8669). J Clin Oncol 2008:26. Abstract 14555
[44]Mita MM, Britten CD, Poplin E, Tap WD, Carmona A, Yonemoto L, Wages DS, Bedrosian CL, Rubin EH, Tolcher AW:Deforolimus trial 106-a phase I trial evaluating 7 regimens of oral deforolimus (AP23573, MK-8669). J Clin Oncol 2008:26. Abstract 3509
[45]O'Donnell A, Faivre S, Burris HA III, Rea D, Papadimitrakopoulou V, Shand N, Lane HA, Hazell K, Zoellner U, Kovarik JM, Brock C, Jones S, Raymond E, Judson I:Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008,26:1588-1595.
[46]Sleijfer S and Wiemer E:Dose selection in phase I studies:why we should always go for the top. J Clin Oncol 26:1576-1578,2008
[47]Cloughesy TF, Yoshimoto K, Nghiemphu P, et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med.2008;5:e8
[48]Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005;353:2012-2024.
[49]Haas-Kogan DA, Prados MD, Tihan T, et al. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst. 2005;97:880-887.
[50]Reardon DA, Quinn JA, Vredenburgh JJ, et al. Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res. 2006; 12:860-868.
[51]Kreisl TN, Lassman AB, Mischel PS, et al. A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). J Neurooncol. 2009;92:99-105.
[52]Sos ML, Koker M, Weir BA, et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res. 2009;69:3256-3261.
[53]Wang MY, Lu KV, Zhu S, et al. Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res. 2006;66:7864-7869.
[54]Fan QW, Knight ZA, Goldenberg DD, et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell.2006;9:341-349.
[55]Fan QW, Cheng CK, Nicolaides TP, et al. A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res. 2007;67:7960-7965.
[56]Reardon DA, Desjardins A, Vredenburgh JJ, et al. Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. JNeurooncol. 2010;96:219-230.
[57]Chang SM, Wen P, Cloughesy T, et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs. 2005;23:357-361.
[58]Galanis E, Buckner JC, Maurer MJ, et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme:a North Central Cancer Treatment Group study. J Clin Oncol.2005;23:5294-5304.
[59]Podsypanina K, Lee RT, Politis C, et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/2 mice. Proc Natl Acad Sci USA.2001;98:10320-10325.
[60]Yu K, Toral-Barza L, Discafani C, et al. mTOR, a novel target in breast cancer:the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer.2001;8:249-258.
[61]Shi Y, Gera J, Hu L, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res.2002;62:5027-5034.
[62]Majumder PK, Febbo PG, Bikoff R, et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med.2004; 10:594-601.
[63]WendelHG,DeStanchinaE, FridmanJS, et al. Survival signallingbyAkt and eIF4E in oncogenesis and cancer therapy. Nature.2004;428:332-337.
[64]Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature.2006;441:475-482.
[65]Maira SM, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther.2008;7:1851-1863.
[66]Smolkova, K.; Plecita-Hlavata, L.; Bellance, N., et al. Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. Int J Biochem Cell Biol 2011,43 (7),950-968.
[67]Berardi, M. J.; Fantin, V. R., Survival of the fittest:metabolic adaptations in cancer. Curr Opin Genet Dev 2011,21 (1),59-66.
[68]Robey, R. B.; Hay, N., Is Akt the "Warburg kinase"?-Akt-energy metabolism interactions and oncogenesis. Semin Cancer Biol 2009,19 (1),25-31.
[69]Sun, Q.; Chen, X.; Ma, J.; Peng, H.; Wang, F.; Zha, X.; Wang, Y.; Jing, Y.; Yang, H.; Chen, R.; Chang, L.; Zhang, Y.; Onda, H.; Chen, T.; Wang, M. R.; Lu, Y.; You, H.; Kwiatkowski, D.; Zhang, H., Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci USA 2011,108(10),4129-4134.
[70]GulatiP,GaspersLD,Dann SG, et al. Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab.2008;7:456-465.
[71]Shackelford DB, Shaw RJ. The LKB1-AMPK pathway:metabolism and growth control in tumour suppression. Nat Rev Cancer.2009;9:563-575.
[72]Guo D, Chien S, Shyy JY. Regulation of endothelial cell cycle by laminar versus oscillatory flow:distinct modes of interactions of AMP-activated protein kinase and Akt pathways. Circ Res.2007; 100:564-571.
[73]Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell.2003;115:577-590.
[74]Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell.2008;30:214-226.
[75]Mahoney CL, Choudhury B, Davies H, et al. LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition. Br J Cancer.2009;100:370-375.
[76]Ikenoue T, Hikiba Y, Kanai F, et al. Functional analysis of mutations within the kinase activation segment of B-Raf in human colorectal tumors. Cancer Res.2003;63:8132-8137.
[77]Dhomen N, Marais R. New insight into BRAF mutations in cancer. Curr Opin Genet Dev.2007;17:31-39.
[78]Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature.2002;417:949-954.
[79]Zheng B, Jeong JH, Asara JM, et al. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell.2009;33:237-247.
[80]Guo D, Hildebrandt IJ, Prins RM, et al. The AMPK agonist AICAR inhibits the growth of EGFRvⅢ-expressing glioblastomas by inhibiting lipogenesis. Proc.Natl Acad Sci USA.2009;106:12932-12937
[81]Guo D, Hildebrandt IJ, Prins RM, et al. The AMPK agonist AICAR inhibits the growth of EGFRvⅢ-expressing glioblastomas by inhibiting lipogenesis. Proc Natl Acad Sci USA.2009; 106:12932-12937.
[2]Fan, Q.W. and W.A. Weiss. Inhibition of PI3K-Akt-mTOR signaling in glioblastoma by mTORCl/2 inhibitors[J]. Methods Mol Biol,2012,821:349-59.
[3]Sheppard, K., K.M. Kinross, B. Solomon, et al. Targeting PI3 kinase/AKT/mTOR signaling in cancer[J]. Crit Rev Oncog,2012,17(1):69-95.
[4]Populo, H., J.M. Lopes, and P. Soares. The mTOR Signalling Pathway in Human Cancer[J]. Int J Mol Sci,2012,13(2):1886-918.
[5]Wu, P. and Y.Z. Hu. PI3K/Akt/mTOR pathway inhibitors in cancer:a perspective on clinical progress[J]. Curr Med Chem,2010,17(35):4326-41.
[6]Ching, C.B. and D.E. Hansel. Expanding therapeutic targets in bladder cancer:the PI3K/Akt/mTOR pathway[J]. Lab Invest,2010,90(10):1406-14.
[7]Bjornsti, M.A. and P.J. Houghton. The TOR pathway:a target for cancer therapy[J]. Nat Rev Cancer,2004,4(5):335-48.
[8]Hay, N. and N. Sonenberg. Upstream and downstream of mTOR[J]. Genes Dev,2004,18(16):1926-45.
[9]Thomas, S.L., R. Alam, N. Lemke, et al. PTEN augments SPARC suppression of proliferation and inhibits SPARC-induced migration by suppressing SHC-RAF-ERK and AKT signaling[J]. Neuro Oncol,2010,12(9):941-55.
[10]Fan, Q.W. and W.A. Weiss. Isoform specific inhibitors of PI3 kinase in glioma[J]. Cell Cycle,2006,5(20):2301-5.
[11]Comprehensive genomic characterization defines human glioblastoma genes and core pathways[J]. Nature,2008,455(7216):1061-8.
[12]Liu, L., L. Gong, Y. Zhang, et al. Glycolysis in Panc-1 human pancreatic cancer cells is inhibited by everolimus[J]. Exp Ther Med,2013,5(1):338-342.
[13]Willems, L., N. Chapuis, A. Puissant, et al. The dual mTORCl and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia[J]. Leukemia,2012,26(6):1195-202.
[14]Pinto-Leite, R., R. Arantes-Rodrigues, C. Palmeira, et al. Everolimus enhances gemcitabine-induced cytotoxicity in bladder-cancer cell lines[J]. J Toxicol Environ Health A,2012,75(13-15):788-99.
[15]Grzybowska-Izydorczyk, O. and P. Smolewski. mTOR kinase inhibitors as a treatment strategy in hematological malignancies [J]. Future Med Chem,2012, 4(4):487-504.
[16]Fan, Q.W., C.K. Cheng, T.P. Nicolaides, et al. A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma[J]. Cancer Res,2007, 67(17):7960-5.
[17]Sehgal, S.N., H. Baker, and C. Vezina. Rapamycin (AY-22,989), a new antifungal antibiotic. Ⅱ. Fermentation, isolation and characterization[J]. J Antibiot (Tokyo),1975,28(10):727-32.
[18]Muthukkumar, S., T.M. Ramesh, and S. Bondada. Rapamycin, a potent immunosuppressive drug, causes programmed cell death in B lymphoma cells[J]. Transplantation,1995,60(3):264-70.
[19]Barbet, N.C., U. Schneider, S.B. Helliwell, et al. TOR controls translation initiation and early G1 progression in yeast[J]. Mol Biol Cell,1996,7(1): 25-42.
[20]Shapira, M., E. Kakiashvili, T. Rosenberg, et al. The mTOR inhibitor rapamycin down-regulates the expression of the ubiquitin ligase subunit Skp2 in breast cancer cells[J]. Breast Cancer Res,2006,8(4):R46.
[21]Warburg, O. On the origin of cancer cells[J]. Science,1956,123(3191): 309-14.
[22]Zhao, S., H. Liu, Y. Liu, et al. miR-143 inhibits glycolysis and depletes sternness of glioblastoma stem-like cells[J]. Cancer Lett,2013.
[23]Hamanaka, R.B. and N.S. Chandel. Targeting glucose metabolism for cancer therapy[J]. J Exp Med,2012,209(2):211-5.
[24]Elstrom, R.L., D.E. Bauer, M. Buzzai, et al. Akt stimulates aerobic glycolysis in cancer cells[J]. Cancer Res,2004,64(11):3892-9.
[25]Rathmell, J.C., C.J. Fox, D.R. Plas, et al. Akt-directed glucose metabolism can prevent Bax conformation change and promote growth factor-independent survival[J]. Mol Cell Biol,2003,23(20):7315-28.
[26]Fang, R., T. Xiao, Z. Fang, et al. MicroRNA-143 (miR-143) regulates cancer glycolysis via targeting hexokinase 2 gene[J]. J Biol Chem,2012,287(27): 23227-35.
[27]Gregersen, L.H., A. Jacobsen, L.B. Frankel, et al. microRNA-143 down-regulates Hexokinase 2 in colon cancer cells[J]. BMC Cancer,2012,12(1):232.
[28]Boon, R.A. and K.C. Vickers. Intercellular transport of microRNAs[J]. Arterioscler Thromb Vasc Biol,2013,33(2):186-92.
[29]Zhang, H., X. Cai, Y. Wang, et al. microRNA-143, down-regulated in osteosarcoma, promotes apoptosis and suppresses tumorigenicity by targeting Bcl-2[J]. Oncol Rep,2010,24(5):1363-9.
[30]Wong, P., M. Iwasaki, T.C. Somervaille, et al. The miR-17-92 microRNA polycistron regulates MLL leukemia stem cell potential by modulating p21 expression[J]. Cancer Res,2010,70(9):3833-42.
[31]Trang, P., P.P. Medina, J.F. Wiggins, et al. Regression of murine lung tumors by the let-7 microRNA[J]. Oncogene,2010,29(11):1580-7.
[32]Garzon, R., G. Marcucci, and C.M. Croce. Targeting microRNAs in cancer:rationale, strategies and challenges[J]. Nat Rev Drug Discov,2010,9(10): 775-89.
[33]Nimmo, R.A. and F.J. Slack. An elegant miRror:microRNAs in stem cells, developmental timing and cancer[J]. Chromosoma,2009,118(4):405-18.
[34]Peschiaroli, A., A. Giacobbe, A. Formosa, et al. miR-143 regulates hexokinase 2 expression in cancer cells[J]. Oncogene,2012.
[35]Cheng, C.C., S.M. Yang, C.Y. Huang, et al. Molecular mechanisms of ginsenoside Rh2-mediated G1 growth arrest and apoptosis in human lung adenocarcinoma A549 cells[J]. Cancer Chemother Pharmacol,2005,55(6):531-40.
[36]Popovich, D.G. and D.D. Kitts. Structure-function relationship exists for ginsenosides in reducing cell proliferation and inducing apoptosis in the human leukemia (THP-1) cell line[J]. Arch Biochem Biophys,2002,406(1):1-8.
[37]Vivanco, I. and C.L. Sawyers. The phosphatidylinositol 3-Kinase AKT pathway in human cancer[J]. Nat Rev Cancer,2002,2(7):489-501.
[38]Zhao, J.J., H. Cheng, S. Jia, et al. The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation[J]. Proc Natl Acad Sci U S A,2006,103(44):16296-300.
[39]Fan, Q.W., Z.A. Knight, D.D. Goldenberg, et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma[J]. Cancer Cell,2006, 9(5):341-9.
[40]Parcellier, A., L.A. Tintignac, E. Zhuravleva, et al. PKB and the mitochondria:AKTing on apoptosis[J]. Cell Signal,2008,20(1):21-30.
[41]Neuhaus, P., J. Klupp, and J.M. Langrehr. mTOR inhibitors:an overview[J]. Liver Transpl,2001,7(6):473-84.
[42]Douros, J. and M. Suffness. New antitumor substances of natural origin[J]. Cancer Treat Rev,1981,8(1):63-87.
[43]Luan, F.L., R. Ding, V.K. Sharma, et al. Rapamycin is an effective inhibitor of human renal cancer metastasis[J]. Kidney Int,2003,63(3):917-26.
[44]Smolewski, P. Recent developments in targeting the mammalian target of rapamycin (mTOR) kinase pathway [J]. Anticancer Drugs,2006,17(5):487-94.
[45]Recher, C., O. Beyne-Rauzy, C. Demur, et al. Antileukemic activity of rapamycin in acute myeloid leukemia[J]. Blood,2005,105(6):2527-34.
[46]Geoerger, B., K. Kerr, C.B. Tang, et al. Antitumor activity of the rapamycin analog CCI-779 in human primitive neuroectodermal tumor/medulloblastoma models as single agent and in combination chemotherapy[J]. Cancer Res,2001,61(4):1527-32.
[47]Wu, C., M. Wangpaichitr, L. Feun, et al. Overcoming cisplatin resistance by mTOR inhibitor in lung cancer[J]. Mol Cancer,2005,4(1):25.
[48]Avellino, R., S. Romano, R. Parasole, et al. Rapamycin stimulates apoptosis of childhood acute lymphoblastic leukemia cells[J]. Blood,2005,106(4): 1400-6.
[49]Markman, B., R. Dienstmann, and J. Tabernero. Targeting the PI3K/Akt/mTOR pathway--beyond rapalogs[J]. Oncotarget,2010,1(7):530-43.
[50]Bartlett, J.M. Biomarkers and patient selection for PI3K/Akt/mTOR targeted therapies:current status and future directions[J]. Clin Breast Cancer,2010, 10 Suppl 3:S86-95.
[51]Hemmings, B.A. and D.F. Restuccia. PI3K-PKB/Akt pathway[J]. Cold Spring Harb Perspect Biol,2012,4(9):a011189.
[52]Fasolo, A. and C. Sessa. Targeting mTOR pathways in human malignancies[J]. Curr Pharm Des,2012,18(19):2766-77.
[53]Hartmann, C., G. Bartels, C. Gehlhaar, et al. PIK3CA mutations in glioblastoma multiforme[J]. Acta Neuropathol,2005,109(6):639-42.
[54]Samuels, Y., Z. Wang, A. Bardelli, et al. High frequency of mutations of the PIK3CA gene in human cancers[J]. Science,2004,304(5670):554.
[55]Manning, B.D. and L.C. Cantley. AKT/PKB signaling:navigating downstream[J]. Cell,2007,129(7):1261-74.
[56]Guertin, D.A. and D.M. Sabatini. The pharmacology of mTOR inhibition[J]. Sci Signal,2009,2(67):pe24.
[57]Alessi, D.R., S.R. James, C.P. Downes, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha[J]. Curr Biol,1997,7(4):261-9.
[58]Calleja, V., M. Laguerre, P.J. Parker, et al. Role of a novel PH-kinase domain interface in PKB/Akt regulation:structural mechanism for allosteric inhibition[J]. PLoS Biol,2009,7(1):e17.
[59]Calleja, V., D. Alcor, M. Laguerre, et al. Intramolecular and intermolecular interactions of protein kinase B define its activation in vivo[J]. PLoS Biol,2007,5(4):e95.
[60]Easton, J.B. and P.J. Houghton. mTOR and cancer therapy[J]. Oncogene, 2006,25(48):6436-46.
[61]Jia, S., Z. Liu, S. Zhang, et al. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis[J]. Nature,2008,454(7205):776-9.
[62]Ciraolo, E., M. Iezzi, R. Marone, et al. Phosphoinositide 3-kinase p110beta activity:key role in metabolism and mammary gland cancer but not development[J]. Sci Signal,2008,1(36):ra3.
[63]Faivre, S., G. Kroemer, and E. Raymond. Current development of mTOR inhibitors as anticancer agents[J]. Nat Rev Drug Discov,2006,5(8):671-88.
[64]Nakamura, J.L., E. Garcia, and R.O. Pieper. S6K1 plays a key role in glial transformation[J]. Cancer Res,2008,68(16):6516-23.
[65]Fan, Q.W., C. Cheng, Z.A. Knight, et al. EGFR signals to mTOR through PKC and independently of Akt in glioma[J]. Sci Signal,2009,2(55):ra4.
[66]Paez, J. and W.R. Sellers. PI3K/PTEN/AKT pathway. A critical mediator of oncogenic signaling[J]. Cancer Treat Res,2003,115:145-67.
[67]Sui, L., J. Wang, and B.M. Li. Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex[J]. Learn Mem,2008,15(10):762-76.
[68]Blay, J.Y. Updating progress in sarcoma therapy with mTOR inhibitors[J]. Ann Oncol,2011,22(2):280-7.
[69]Shi, Y., J. Gera, L. Hu, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779[J]. Cancer Res,2002,62(17):5027-34.
[70]Gera, J.F., I.K. Mellinghoff, Y. Shi, et al. AKT activity determines sensitivity to mammalian target of rapamycin (mTOR) inhibitors by regulating cyclin Dl and c-myc expression[J]. J Biol Chem,2004,279(4):2737-46.
[71]Bartel, D.P. MicroRNAs:genomics, biogenesis, mechanism, and function[J]. Cell,2004,116(2):281-97.
[72]Gambhir, S.S. Molecular imaging of cancer with positron emission tomography[J]. Nat Rev Cancer,2002,2(9):683-93.
[73]Frezza, C. and E. Gottlieb. Mitochondria in cancer:not just innocent bystanders[J]. Semin Cancer Biol,2009,19(1):4-11.
[74]Vander Heiden, M.G., L.C. Cantley, and C.B. Thompson. Understanding the Warburg effect:the metabolic requirements of cell proliferation[J]. Science,2009, 324(5930):1029-33.
[75]Pfeiffer, T., S. Schuster, and S. Bonhoeffer. Cooperation and competition in the evolution of ATP-producing pathways[J]. Science,2001,292(5516):504-7.
[76]Zu, X.L. and M. Guppy. Cancer metabolism:facts, fantasy, and fiction[J]. Biochem Biophys Res Commun,2004,313(3):459-65.
[77]Reitzer, L.J., B.M. Wice, and D. Kennell. Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells[J]. J Biol Chem,1979, 254(8):2669-76.
[78]Lunt, S.Y. and M.G. Vander Heiden. Aerobic glycolysis:meeting the metabolic requirements of cell proliferation[J]. Annu Rev Cell Dev Biol,2011,27: 441-64.
[79]Treiber, T., N. Treiber, and G. Meister. Regulation of microRNA biogenesis and function[J]. Thromb Haemost,2012,107(4):605-10.
[80]Lewis, B.P., C.B. Burge, and D.P. Bartel. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets[J]. Cell,2005,120(1):15-20.
[81]Michael, M.Z., O.C. SM, N.G. van Holst Pellekaan, et al. Reduced accumulation of specific microRNAs in colorectal neoplasia[J]. Mol Cancer Res, 2003,1(12):882-91.
[82]Motoyama, K., H. Inoue, Y. Takatsuno, et al. Over-and under-expressed microRNAs in human colorectal cancer[J]. Int J Oncol,2009,34(4):1069-75.
[83]Slaby, O., M. Svoboda, P. Fabian, et al. Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer[J]. Oncology,2007,72(5-6):397-402.
[84]Wang, C.J., Z.G. Zhou, L. Wang, et al. Clinicopathological significance of microRNA-31,-143 and-145 expression in colorectal cancer[J]. Dis Markers,2009, 26(1):27-34.
[85]Kulda, V., M. Pesta, O. Topolcan, et al. Relevance of miR-21 and miR-143 expression in tissue samples of colorectal carcinoma and its liver metastases[J]. Cancer Genet Cytogenet,2010,200(2):154-60.
[86]Tokarz, P. and J. Blasiak. The role of microRNA in metastatic colorectal cancer and its significance in cancer prognosis and treatment[J]. Acta Biochim Pol, 2012,59(4):467-74.
[87]Lui, W.O., N. Pourmand, B.K. Patterson, et al. Patterns of known and novel small RNAs in human cervical cancer[J]. Cancer Res,2007,67(13):6031-43.
[88]Akao, Y., Y. Nakagawa, Y. Kitade, et al. Downregulation of microRNAs-143 and-145 in B-cell malignancies[J]. Cancer Sci,2007,98(12): 1914-20.
[89]Wang, X., S. Tang, S.Y. Le, et al. Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth[J]. PLoS One,2008,3(7):e2557.
[90]Amaral, F.C., N. Torres, F. Saggioro, et al. MicroRNAs differentially expressed in ACTH-secreting pituitary tumors[J]. J Clin Endocrinol Metab,2009, 94(1):320-3.
[91]Chen, H.C., G.H. Chen, Y.H. Chen, et al. MicroRNA deregulation and pathway alterations in nasopharyngeal carcinoma[J]. Br J Cancer,2009,100(6): 1002-11.
[92]Takagi, T., A. Iio, Y. Nakagawa, et al. Decreased expression of microRNA-143 and-145 in human gastric cancers[J]. Oncology,2009,77(1):12-21.
[93]Yu, T., X.Y. Wang, R.G. Gong, et al. The expression profile of microRNAs in a model of 7,12-dimethyl-benz[a]anthrance-induced oral carcinogenesis in Syrian hamster[J]. J Exp Clin Cancer Res,2009,28:64.
[94]Song, T., W. Xia, N. Shao, et al. Differential miRNA expression profiles in bladder urothelial carcinomas[J]. Asian Pac J Cancer Prev,2010,11(4):905-11.
[95]Han, Y., J. Chen, X. Zhao, et al. MicroRNA expression signatures of bladder cancer revealed by deep sequencing[J]. PLoS One,2011,6(3):e18286.
[96]Bockmeyer, C.L., M. Christgen, M. Muller, et al. MicroRNA profiles of healthy basal and luminal mammary epithelial cells are distinct and reflected in different breast cancer subtypes[J]. Breast Cancer Res Treat,2011,130(3):735-45.
[97]Wach, S., E. Nolte, J. Szczyrba, et al. MicroRNA profiles of prostate carcinoma detected by multiplatform microRNA screening[J]. Int J Cancer,2012, 130(3):611-21.
[98]Vosa, U., T. Vooder, R. Kolde, et al. Meta-analysis of microRNA expression in lung cancer[J]. Int J Cancer,2012.
[99]Pignot, G., G. Cizeron-Clairac, S. Vacher, et al. microRNA expression profile in a large series of bladder tumors:Identification of a 3-miRNA signature associated with aggressiveness of muscle-invasive bladder cancer[J]. Int J Cancer, 2013,132(11):2479-91.
[100]Salomon, D.S., R. Brandt, F. Ciardiello, et al. Epidermal growth factor-related peptides and their receptors in human malignancies[J]. Crit Rev Oncol Hematol,1995,19(3):183-232.
[101]Klos, K.S., S.L. Wyszomierski, M. Sun, et al. ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells[J]. Cancer Res,2006,66(4):2028-37.
[102]Zhao, Y. and Y. Sun. Targeting the mTOR-DEPTOR pathway by CRL E3 ubiquitin ligases:therapeutic application[J]. Neoplasia,2012,14(5):360-7.
[103]Papadimitrakopoulou, V. Development of PI3K/AKT/mTOR pathway inhibitors and their application in personalized therapy for non-small-cell lung cancer[J]. J Thorac Oncol,2012,7(8):1315-26.
[104]Fine, B., C. Hodakoski, S. Koujak, et al. Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a[J]. Science,2009, 325(5945):1261-5.
[105]Soria, J.C., F.A. Shepherd, J.Y. Douillard, et al. Efficacy of everolimus (RAD001) in patients with advanced NSCLC previously treated with chemotherapy alone or with chemotherapy and EGFR inhibitors[J]. Ann Oncol,2009,20(10): 1674-81.
[106]Shaw, R.J. and L.C. Cantley. Ras, PI(3)K and mTOR signalling controls tumour cell growth[J]. Nature,2006,441(7092):424-30.
[107]Zhao, L. and P.K. Vogt. Class I PI3K in oncogenic cellular transformation[J]. Oncogene,2008,27(41):5486-96.
[108]Awada, A., F. Cardoso, C. Fontaine, et al. The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer:results of a phase I study with pharmacokinetics[J]. Eur J Cancer,2008,44(1): 84-91.
[109]Robey, R.B. and N. Hay. Mitochondrial hexokinases, novel mediators of the antiapoptotic effects of growth factors and Akt[J]. Oncogene,2006,25(34): 4683-96.
[110]Jae, H.J., J.W. Chung, H.S. Park, et al. The antitumor effect and hepatotoxicity of a hexokinase II inhibitor 3-bromopyruvate:in vivo investigation of intraarterial administration in a rabbit VX2 hepatoma model [J]. Korean J Radiol,2009, 10(6):596-603.
[111]Christofk, H.R., M.G. Vander Heiden, M.H. Harris, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth[J]. Nature,2008,452(7184):230-3.
[112]Bluemlein, K., N.M. Gruning, R.G. Feichtinger, et al. No evidence for a shift in pyruvate kinase PKM1 to PKM2 expression during tumorigenesis[J]. Oncotarget,2011,2(5):393-400.
[113]Spoden, G.A., U. Rostek, S. Lechner, et al. Pyruvate kinase isoenzyme M2 is a glycolytic sensor differentially regulating cell proliferation, cell size and apoptotic cell death dependent on glucose supply [J]. Exp Cell Res,2009,315(16): 2765-74.
[114]Hitosugi, T., S. Kang, M.G. Vander Heiden, et al. Tyrosine phosphorylation inhibits PKM2 to promote the Warburg effect and tumor growth[J]. Sci Signal,2009,2(97):ra73.
[115]Lv, L., D. Li, D. Zhao, et al. Acetylation targets the M2 isoform of pyruvate kinase for degradation through chaperone-mediated autophagy and promotes tumor growth[J]. Mol Cell,2011,42(6):719-30.
[116]Vander Heiden, M.G., J.W. Locasale, K.D. Swanson, et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells[J]. Science,'2010, 329(5998):1492-9.
[117]Anastasiou, D., G. Poulogiannis, J.M. Asara, et al. Inhibition of pyruvate kinase M2 by reactive oxygen species contributes to cellular antioxidant responses [J]. Science,2011,334(6060):1278-83.
[118]Goldberg, M.S. and P.A. Sharp. Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression[J]. J Exp Med,2012,209(2):217-24.
[119]Luo, W., H. Hu, R. Chang, et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1[J]. Cell,2011,145(5): 732-44.
[120]Lee, J., H.K. Kim, Y.M. Han, et al. Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription[J]. Int J Biochem Cell Biol,2008,40(5):1043-54.
[121]Yang, W., Y. Xia, H. Ji, et al. Nuclear PKM2 regulates beta-catenin transactivation upon EGFR activation[J]. Nature,2011,480(7375):118-22.
[122]Shim, H., C. Dolde, B.C. Lewis, et al. c-Myc transactivation of LDH-A: implications for tumor metabolism and growth[J]. Proc Natl Acad Sci U S A,1997, 94(13):6658-63.
[123]Locasale, J.W. and L.C. Cantley. Metabolic flux and the regulation of mammalian cell growth[J]. Cell Metab,2011,14(4):443-51.
[124]Le, A., C.R. Cooper, A.M. Gouw, et al. Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression[J]. Proc Natl Acad Sci USA,2010,107(5):2037-42.
[125]Younes, M., L.V. Lechago, J.R. Somoano, et al. Wide expression of the human erythrocyte glucose transporter Glut1 in human cancers[J]. Cancer Res,1996, 56(5):1164-7.
[126]Chan, D.A., P.D. Sutphin, P. Nguyen, et al. Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality[J]. Sci Transl Med,2011,3(94):94ra70.
[127]Locasale, J.W., A.R. Grassian, T. Melman, et al. Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis[J]. Nat Genet, 2011,43(9):869-74.
[128]Possemato, R., K.M. Marks, Y.D. Shaul, et al. Functional genomics reveal that the serine synthesis pathway is essential in breast cancer[J]. Nature,2011, 476(7360):346-50.
[129]Vora, S., J.P. Halper, and D.M. Knowles. Alterations in the activity and isozymic profile of human phosphofructokinase during malignant transformation in vivo and in vitro:transformation-and progression-linked discriminants of malignancy[J]. Cancer Res,1985,45(7):2993-3001.
[130]Colombo, S.L., M. Palacios-Callender, N. Frakich, et al. Anaphase-promoting complex/cyclosome-Cdh1 coordinates glycolysis and glutaminolysis with transition to S phase in human T lymphocytes [J]. Proc Natl Acad Sci USA,2010,107(44):18868-73.
[131]Yao, N., C.L. Lu, J.J. Zhao, et al. A network of miRNAs expressed in the ovary are regulated by FSH[J]. Front Biosci,2009,14:3239-45.
[132]Zhang, J., X. Ji, D. Zhou, et al. miR-143 is critical for the formation of primordial follicles in mice[J]. Front Biosci,2013,18:588-97.
[133]Ohlsson Teague, E.M., K.H. Van der Hoek, M.B. Van der Hoek, et al. MicroRNA-regulated pathways associated with endometriosis[J]. Mol Endocrinol, 2009,23(2):265-75.
[134]He, Z., J. Yu, C. Zhou, et al. MiR-143 is not essential for adipose development as revealed by in vivo antisense targeting[J]. Biotechnol Lett,2013, 35(4):499-507.
[135]Walden, T.B., J.A. Timmons, P. Keller, et al. Distinct expression of muscle-specific microRNAs (myomirs) in brown adipocytes[J]. J Cell Physiol,2009, 218(2):444-9.
[136]Esau, C., X. Kang, E. Peralta, et al. MicroRNA-143 regulates adipocyte differentiation[J]. J Biol Chem,2004,279(50):52361-5.
[137]Takanabe, R., K. Ono, Y. Abe, et al. Up-regulated expression of microRNA-143 in association with obesity in adipose tissue of mice fed high-fat diet[J]. Biochem Biophys Res Commun,2008,376(4):728-32.
[138]Merkerova, M., A. Vasikova, M. Belickova, et al. MicroRNA expression profiles in umbilical cord blood cell lineages[J]. Stem Cells Dev,2010,19(1):17-26.
[139]Donahue, R.E., P. Jin, A.C. Bonifacino, et al. Plerixafor (AMD3100) and granulocyte colony-stimulating factor (G-CSF) mobilize different CD34+cell populations based on global gene and microRNA expression signatures[J]. Blood, 2009,114(12):2530-41.
[140]Bruchova, H., M. Merkerova, and J.T. Prchal. Aberrant expression of microRNA in polycythemia vera[J]. Haematologica,2008,93(7):1009-16.
[141]Akao, Y., Y. Nakagawa, A. Iio, et al. Role of microRNA-143 in Fas-mediated apoptosis in human T-cell leukemia Jurkat cells[J]. Leuk Res,2009, 33(11):1530-8.
[142]Dostalova Merkerova, M., Z. Krejcik, H. Votavova, et al. Distinctive microRNA expression profiles in CD34+ bone marrow cells from patients with myelodysplastic syndrome[J]. Eur J Hum Genet,2011,19(3):313-9.
[143]Cordes, K.R., N.T. Sheehy, M.P. White, et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity[J]. Nature,2009,460(7256):705-10.
[144]Wang, X., G. Hu, and J. Zhou. Repression of versican expression by microRNA-143[J]. J Biol Chem,2010,285(30):23241-50.
[145]Rangrez, A.Y., Z.A. Massy, V. Metzinger-Le Meuth, et al. miR-143 and miR-145:molecular keys to switch the phenotype of vascular smooth muscle cells[J]. Circ Cardiovasc Genet,2011,4(2):197-205.
[146]Boettger, T., N. Beetz, S. Kostin, et al. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir 143/145 gene cluster[J]. J Clin Invest,2009,119(9):2634-47.
[147]Palmieri, A., F. Pezzetti, A. Avantaggiato, et al. Titanium acts on osteoblast translational process[J]. J Oral Implantol,2008,34(4):190-5.
[148]Schmidt, W.M., A.O. Spiel, B. Jilma, et al. In vivo profile of the human leukocyte microRNA response to endotoxemia[J]. Biochem Biophys Res Commun, 2009,380(3):437-41.
[149]Nakagawa, Y., M. Iinuma, T. Naoe, et al. Characterized mechanism of alpha-mangostin-induced cell death:caspase-independent apoptosis with release of endonuclease-G from mitochondria and increased miR-143 expression in human colorectal cancer DLD-1 cells[J]. Bioorg Med Chem,2007,15(16):5620-8.
[150]Chen, X., X. Guo, H. Zhang, et al. Role of miR-143 targeting KRAS in colorectal tumorigenesis[J]. Oncogene,2009,28(10):1385-92.
[151]Xu, B., X. Niu, X. Zhang, et al. miR-143 decreases prostate cancer cells proliferation and migration and enhances their sensitivity to docetaxel through suppression of KRAS[J]. Mol Cell Biochem,2011,350(1-2):207-13.
[152]Ng, E.K., W.P. Tsang, S.S. Ng, et al. MicroRNA-143 targets DNA methyltransferases 3A in colorectal cancer[J]. Br J Cancer,2009,101(4):699-706.
[153]Noguchi, S., T. Mori, Y. Hoshino, et al. MicroRNA-143 functions as a tumor suppressor in human bladder cancer T24 cells[J]. Cancer Lett,2011,307(2): 211-20.
[154]Ni, Y., L. Meng, L. Wang, et al. MicroRNA-143 functions as a tumor suppressor in human esophageal squamous cell carcinoma[J]. Gene,2013,517(2): 197-204.
[155]Osaki, M., F. Takeshita, Y. Sugimoto, et al. MicroRNA-143 regulates human osteosarcoma metastasis by regulating matrix metalloprotease-13 expression[J]. Mol Ther,2011,19(6):1123-30.
[156]Hu, Y., Y. Ou, K. Wu, et al. miR-143 inhibits the metastasis of pancreatic cancer and an associated signaling pathway[J]. Tumour Biol,2012,33(6): 1863-70.
[157]Suzuki, H.I., K. Yamagata, K. Sugimoto, et al. Modulation of microRNA processing by p53[J]. Nature,2009,460(7254):529-33.
[158]Yamagata, T., J. Yoshizawa, S. Ohashi, et al. Expression patterns of microRNAs are altered in hypoxic human neuroblastoma cells[J]. Pediatr Surg Int, 2010,26(12):1179-84.
[159]Bradshaw-Pierce, E.L., T.M. Pitts, G. Kulikowski, et al. Utilization of quantitative in vivo pharmacology approaches to assess combination effects of everolimus and irinotecan in mouse xenograft models of colorectal cancer[J]. PLoS One,2013,8(3):e58089.
[1]Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ. Exciting new advances in neuro-oncology:the avenue to a cure for malignant glioma. CA Cancer J Clin 2010;60:166-93..
[2]Bjornsti M-A, Houghton PJ:The TOR pathway:a target for cancer therapy. Nat Rev Cancer 2004,4:335-348.
[3]Guertin DA, Sabatini DM:Defining the role of mTOR in cancer. Cancer Cell 2007,12:9-22.
[4]Hay N, Sonenberg N:Upstream and downstream of mTOR. Genes Dev 2004, 18:1926-1945.
[5]Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC:The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell 2004,6:91-99.
[6]Grewe M, Gansauge F, Schmid RM, Adler G, Seufferlein T:Regulation of cell growth and cyclin D1 expression by the constitutively active FRAP-p70s6K pathway in human pancreatic cancer cells. Cancer Res 1999,59:3581-3587.
[7]Taha C, Liu Z, Jin J, Al-Hasani H, Sonenberg N, Klip A:Opposite translational control of GLUT1 and GLUT4 glucose transporter mRNAs in response to insulin. J Biol Chem 1999,274:33085-33091.
[8]Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet.2006;7:606-619
[9]Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer.2002;2:489-501.
[10]The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061-1068.
[11]Parsons DW, Jones S, Zhang X, et al. An integrated genomic analysis of human glioblastoma multiforme. Science.2008;321:1807-1812.
[12]Huang HS, Nagane M, Klingbeil CK, et al. The enhanced tumorigenic activity of a mutant epidermal growth factor receptor common in human cancers is mediated by threshold levels of constitutive tyrosine phosphorylation and unattenuated signaling. J Biol Chem.1997;272:2927-2935.
[13]Montgomery RB, Moscatello DK, Wong AJ, Cooper JA, Stahl WL. Differential modulation of mitogen-activated protein (MAP) kinase extracellular signal-related kinase kinase and MAP kinase activities by a mutant epidermal growth factor receptor. J Biol Chem.1995;270:30562-30566.
[14]Wikstrand CJ, McLendon RE, Friedman AH, Bigner DD. Cell surface localization and density of the tumor-associated variant of the epidermal growth factor receptor, EGFRvIII. Cancer Res.1997;57:4130-4140.
[15]Carracedo A, Ma L, Teruya-Feldstein J, et al. Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest.2008; 118:3065-3074.
[16]Yoshimoto K, Dang J, Zhu S, et al. Development of a real-time RT-PCR assay for detecting EGFRvⅢ in glioblastoma samples. Clin Cancer Res. 2008;14:488-493.
[17]Huang PH, Mukasa A, Bonavia R, et al. Quantitative analysis of EGFRvⅢ cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma. Proc Natl Acad Sci USA.2007; 104:12867-12872.
[18]Ermoian RP, Furniss CS, Lamborn KR, et al. Dysregulation of PTEN and protein kinase B is associated with glioma histology and patient survival. Clin Cancer Res.2002;8:1100-1106
[19]Holland EC. Gliomagenesis:genetic alterations and mouse models. Nat Rev Genet.2001;2:120-129.
[20]Sonoda Y, Ozawa T, Aldape KD, Deen DF, Berger MS, Pieper RO. Akt pathway activation converts anaplastic astrocytoma to glioblastoma multiforme in a human astrocyte model of glioma. Cancer Res.2001;61:6674-6678.
[21]Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition. Sci Signal.2009;2:e24.
[22]Peterson TR, Laplante M, Thoreen CC, et al. DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival. Cell.2009;137:873-886.
[23]Alessi DR, James SR, Downes CP, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol.1997;7:261-269.
[24]Calleja V, Laguerre M, Parker PJ, Larijani B. Role of a novel PH-kinase domain interface in PKB/Akt regulation:structural mechanism for allosteric inhibition. PLoSBiol.2009;7:e17.
[25]Calleja V, Alcor D, Laguerre M, et al. Intramolecular and intermolecular interactions of protein kinase B define its activation in vivo. PLoS Biol.2007;5:e95.
[26]Easton JB, Houghton PJ. mTOR and cancer therapy. Oncogene.2006;25:6436-6446.
[27]Fan QW, Cheng C, Knight ZA, et al. EGFR signals to mTOR through PKC and independently of Akt in glioma. Sci Signal.2009;2:ra4.
[28]Nakamura JL, Garcia E, Pieper RO. S6K1 plays a key role in glial transformation.Cancer Res.2008;68:6516-6523.
[29]Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science.2005;307:1098-1101.
[30]Sabatini DM. mTOR and cancer:insights into a complex relationship.Nat Rev Cancer.2006;6:729-734.
[31]Zhang H, Bajraszewski N, Wu E, et al. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest. 2007; 117:730-738.
[32]Masri J, Bernath A, Martin J, et al. mTORC2 activity is elevated in gliomas and promotes growth and cell motility via overexpression of rictor. Cancer Res.2007;67:11712-11720.
[33]Read RD, Cavenee WK, Furnari FB, Thomas JB. A drosophila model for EGFR-Ras and PI3K-dependent human glioma. PLoS Genet.2009;5:e1000374
[34]Faivre S, Kroemer G, Raymond E:Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006,5:671-688.
[35]Seghal SN, Baker H, Vezina C:Rapamycin (AY-22,989), a new antifungal antiobiotic II. Fermentation, isolation and characterization. J Antibiot [Tokyo] 1975,28:727-732.
[36]Douros J, Suffnes M:New antitumor substances of natural origin. Cancer Treat Rev 1981,8:63-87.
[37]Pascual J:Everolimus in clinical practice--renal transplantation. Nephrol Dial Transplant 2006,21(suppl 3):iii18-iii23.
[38]Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantinevon Kaeppler HA, Starling RC, S(?)rensen K, Hummel M, Lind JM, Abeywickrama KH, Bernhardt P, RAD B253 Study Group:Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N Engl J Med 2003,349:847-858.
[39]Novartis Media Release. Certican approved by Swissmedic to reduce organ rejection risk in heart and kidney transplant patients 2005 [http://www.medicalnewstoday.com/articles/24886.php]. Accessed October 14,2009
[40]Hidalgo M, Buckner JC, Erlichman C, Pollack MS, Boni JP, Dukart G, Marshall B, Speicher L, Moore L, Rowinsky EK:A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 2006,12:5755-5763.
[41]TORISEL(?) (temsirolimus) prescribing information. Wyeth Pharmaceuticals Inc., Philadelphia, PA; 2008.
[42]Mita MM, Mita AC, Chu QS, Rowinsky EK, Fetterly GJ, Goldston M, Patnaik A, Mathews L, Ricart AD, Mays T, Knowles H, Rivera VM, Kreisberg J, Bedrosian CL, Tolcher AW:Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 2008, 26:361-367.
[43]Fetterly GJ, Mita MM, Britten CD, Poplin E, Tap WD, Carmona A, Yonemoto L, Bedrosian CL, Rubin EH, Tolcher AW:Pharmacokinetics of oral deforolimus (AP23573, MK-8669). J Clin Oncol 2008:26. Abstract 14555
[44]Mita MM, Britten CD, Poplin E, Tap WD, Carmona A, Yonemoto L, Wages DS, Bedrosian CL, Rubin EH, Tolcher AW:Deforolimus trial 106-a phase I trial evaluating 7 regimens of oral deforolimus (AP23573, MK-8669). J Clin Oncol 2008:26. Abstract 3509
[45]O'Donnell A, Faivre S, Burris HA III, Rea D, Papadimitrakopoulou V, Shand N, Lane HA, Hazell K, Zoellner U, Kovarik JM, Brock C, Jones S, Raymond E, Judson I:Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 2008,26:1588-1595.
[46]Sleijfer S and Wiemer E:Dose selection in phase I studies:why we should always go for the top. J Clin Oncol 26:1576-1578,2008
[47]Cloughesy TF, Yoshimoto K, Nghiemphu P, et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med.2008;5:e8
[48]Mellinghoff IK, Wang MY, Vivanco I, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005;353:2012-2024.
[49]Haas-Kogan DA, Prados MD, Tihan T, et al. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst. 2005;97:880-887.
[50]Reardon DA, Quinn JA, Vredenburgh JJ, et al. Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res. 2006; 12:860-868.
[51]Kreisl TN, Lassman AB, Mischel PS, et al. A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). J Neurooncol. 2009;92:99-105.
[52]Sos ML, Koker M, Weir BA, et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res. 2009;69:3256-3261.
[53]Wang MY, Lu KV, Zhu S, et al. Mammalian target of rapamycin inhibition promotes response to epidermal growth factor receptor kinase inhibitors in PTEN-deficient and PTEN-intact glioblastoma cells. Cancer Res. 2006;66:7864-7869.
[54]Fan QW, Knight ZA, Goldenberg DD, et al. A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell.2006;9:341-349.
[55]Fan QW, Cheng CK, Nicolaides TP, et al. A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res. 2007;67:7960-7965.
[56]Reardon DA, Desjardins A, Vredenburgh JJ, et al. Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. JNeurooncol. 2010;96:219-230.
[57]Chang SM, Wen P, Cloughesy T, et al. Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs. 2005;23:357-361.
[58]Galanis E, Buckner JC, Maurer MJ, et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme:a North Central Cancer Treatment Group study. J Clin Oncol.2005;23:5294-5304.
[59]Podsypanina K, Lee RT, Politis C, et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten+/2 mice. Proc Natl Acad Sci USA.2001;98:10320-10325.
[60]Yu K, Toral-Barza L, Discafani C, et al. mTOR, a novel target in breast cancer:the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endocr Relat Cancer.2001;8:249-258.
[61]Shi Y, Gera J, Hu L, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res.2002;62:5027-5034.
[62]Majumder PK, Febbo PG, Bikoff R, et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med.2004; 10:594-601.
[63]WendelHG,DeStanchinaE, FridmanJS, et al. Survival signallingbyAkt and eIF4E in oncogenesis and cancer therapy. Nature.2004;428:332-337.
[64]Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature.2006;441:475-482.
[65]Maira SM, Stauffer F, Brueggen J, et al. Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther.2008;7:1851-1863.
[66]Smolkova, K.; Plecita-Hlavata, L.; Bellance, N., et al. Waves of gene regulation suppress and then restore oxidative phosphorylation in cancer cells. Int J Biochem Cell Biol 2011,43 (7),950-968.
[67]Berardi, M. J.; Fantin, V. R., Survival of the fittest:metabolic adaptations in cancer. Curr Opin Genet Dev 2011,21 (1),59-66.
[68]Robey, R. B.; Hay, N., Is Akt the "Warburg kinase"?-Akt-energy metabolism interactions and oncogenesis. Semin Cancer Biol 2009,19 (1),25-31.
[69]Sun, Q.; Chen, X.; Ma, J.; Peng, H.; Wang, F.; Zha, X.; Wang, Y.; Jing, Y.; Yang, H.; Chen, R.; Chang, L.; Zhang, Y.; Onda, H.; Chen, T.; Wang, M. R.; Lu, Y.; You, H.; Kwiatkowski, D.; Zhang, H., Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci USA 2011,108(10),4129-4134.
[70]GulatiP,GaspersLD,Dann SG, et al. Amino acids activate mTOR complex 1 via Ca2+/CaM signaling to hVps34. Cell Metab.2008;7:456-465.
[71]Shackelford DB, Shaw RJ. The LKB1-AMPK pathway:metabolism and growth control in tumour suppression. Nat Rev Cancer.2009;9:563-575.
[72]Guo D, Chien S, Shyy JY. Regulation of endothelial cell cycle by laminar versus oscillatory flow:distinct modes of interactions of AMP-activated protein kinase and Akt pathways. Circ Res.2007; 100:564-571.
[73]Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell.2003;115:577-590.
[74]Gwinn DM, Shackelford DB, Egan DF, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell.2008;30:214-226.
[75]Mahoney CL, Choudhury B, Davies H, et al. LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition. Br J Cancer.2009;100:370-375.
[76]Ikenoue T, Hikiba Y, Kanai F, et al. Functional analysis of mutations within the kinase activation segment of B-Raf in human colorectal tumors. Cancer Res.2003;63:8132-8137.
[77]Dhomen N, Marais R. New insight into BRAF mutations in cancer. Curr Opin Genet Dev.2007;17:31-39.
[78]Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature.2002;417:949-954.
[79]Zheng B, Jeong JH, Asara JM, et al. Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell.2009;33:237-247.
[80]Guo D, Hildebrandt IJ, Prins RM, et al. The AMPK agonist AICAR inhibits the growth of EGFRvⅢ-expressing glioblastomas by inhibiting lipogenesis. Proc.Natl Acad Sci USA.2009;106:12932-12937
[81]Guo D, Hildebrandt IJ, Prins RM, et al. The AMPK agonist AICAR inhibits the growth of EGFRvⅢ-expressing glioblastomas by inhibiting lipogenesis. Proc Natl Acad Sci USA.2009; 106:12932-12937.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |