核因子NF-κB信号通路模型的建立及其小分子抑制剂山楂酸在肿瘤、免疫中的应用研究
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摘要
核因子NF-κB (Nuclear Factor-κB)作为一个关键的转录调节分子参与多种生物学功能。现在已经证实其广泛存在于真核细胞内,能与多种基因启动子或增强子序列的特定位点结合而促进转录和表达,参与炎症反应、免疫应答以及细胞的增殖、转化和凋亡等重要的病理生理过程。NF-κB的活性受到严格精密的调控,是一个受到多因素共同维持的平衡,只有严格维系这种平衡,细胞才能正常生存和行使生理功能。一旦这种平衡被打破,就会导致生理功能紊乱,产生疾病。研究发现大部分肿瘤组织中NF-κB活性升高,另外,在一些炎性疾病、感染性疾病,如哮喘,各种关节炎,肩周炎,牙周炎以及艾滋病感染早期患者中也发现NF-κB的活性显著升高,而在另外一些自身免疫性疾病中发现NF-κB活性降低。前期研究已经证实维持NF-κB活性的平衡具有重要作用,其活性异常与众多疾病密切相关。因此,NF-κB已经成为治疗包括癌症在内的多种疾病药物作用和开发的分子靶点。
NF-κB的活化是一个多步骤的过程,当激活因子从细胞表面进入细胞内后,首先激活上游激酶(IKK),再通过激酶磷酸化NF-κB的抑制亚单位IκBα,进而导致NF-κB从细胞质进入到细胞核,与特定的靶标结合,调控相关基因表达,最后调控相关的生理过程。根据NF-κB这些特点,本课题进行了以下方面的研究：
一、建立了NF-κB活性的各种检测方法,包括：NF-κB报告基因分析方法,免疫荧光的方法(检测NF-κB在细胞内的定位),电泳迁移率实验(EMSA-electrophoretic mobility shift assay),蛋白印迹的方法(分析抑制亚单位IκBα的降解情况和调控基因表达情况)和染色质免疫共沉淀的方法(chromatin immunoprecipitation assay, ChIP)来研究分析NF-κB对疾病的调控作用和筛选发现调控NF-κB活性的药物。另一方面,我们还建立了包括裸鼠荷瘤,肿瘤转移和骨质疏松的动物模型,以期望进一步在体内对NF-κB进行机理和应用方面的深入研究。
二、利用建好的NF-κB实验模型,我们筛选得到了数个NF-κB信号通路的抑制剂,并选取了其中一个活性小分子——山楂酸,进一步对山楂酸在抗肿瘤方面的机理进行了研究。我们研究发现：
1、山楂酸具有抑制胰腺癌细胞增值的作用。在TNFα存在时,这种抑制效果更加明显,统计表明显著增强；
2、山楂酸与TNFα协同抑制胰腺癌细胞增殖的作用,是通过促进细胞凋亡来实现的；
3、山楂酸是通过抑制NF-κB的活化来促进胰腺癌细胞凋亡的；
4、在体外,山楂酸处理能够抑制NF-κB下游的相关基因的表达；
5、裸鼠体内实验进一步证明山楂酸处理能够抑制胰腺癌肿瘤的生长,促进胰腺肿瘤细胞凋亡。
这些结果提示山楂酸处理能够分别在体内和体外抑制肿瘤细胞的生长,他的抗癌机理是通过抑制NF-κB信号通路的活化和NF-κB下游相关基因的表达来实现的,这就提示,山楂酸和TNFα一起联合使用可能对胰腺癌的治疗有所帮助。
三、我们课题的另外一个部分研究发现山楂酸能够抑制破骨细胞的分化和功能。这些研究结果包括：
1、研究发现山楂酸能够抑制破骨细胞分化,而且具有时间和浓度剂量依赖性；
2、山楂酸还能够抑制破骨细胞特殊的功能结构肌动蛋白环(ACTIN-RING)的形成；
3、pits assay证实,在体外山楂酸能够抑制破骨细胞对骨片的吸收；4、在体内,我们进一步发现,山楂酸能够抑制由于卵巢切除导致的小鼠骨质流失；
5、进一步研究表明,山楂酸能够抑制由于卵巢切除导致的破骨细胞活性升高。
这些现象提示,山楂酸能够抑制破骨细胞的分化和功能,而且对卵巢切除导致的骨质疏松有预防和治疗作用。我们进一步探讨了这些现象的机理。研究发现：
1、山楂酸处理能够抑制RANKL诱导引起的NF-κB信号通路的活化；
2、山楂酸处理能够抑制RANKL诱导的引起的MAPK-AP1信号通路的活化；
3、山楂酸处理能够抑制NFAT-c1的表达,但是不影响其活性；
4、山楂酸处理能够抑制破骨细胞分化和功能相关基因的表达；
5、山楂酸处理不影响RANKL诱发的细胞内钙流水平；
通过上述研究,我们初步证明了山楂酸能够通过抑制NF-κB信号通路和MAPK-AP1信号通路的活化来抑制破骨细胞的分化和功能,而且我们在动物水平验证了山楂酸能够抑制由于激素水平下降导致的骨质流失,这些结果为山楂酸在预防和治疗破骨细胞相关疾病如骨质疏松症方面提供了理论支持。
综上所述,我们成功的建立了在分子、细胞和动物水平的NF-κB信号通路研究模型,为下一步进行跟NF-κB信号通路相关的机理研究和运用研究奠定了基础。利用建立的模型,我们筛选获得了数个NF-κB信号通路的小分子抑制剂。紧接着,我们对其中之一的山楂酸的功能和机理进行了深入研究。我们发现：山楂酸和肿瘤坏死因子α联合使用具有良好的抗肿瘤效果。而且我们的研究还发现,山楂酸能够抑制破骨前体细胞的分化和功能,在体内能够抑制由于卵巢切除导致的骨质疏松。这些研究为以后山楂酸在肿瘤治疗,破骨细胞相关疾病的预防和治疗方面提供了理论支持。同时,我们的这部分研究也为以后利用NF-κB信号通路研究模型提供了有益探索和尝试。
Abstract
Nuclear Factor-KB (NF-κB), an well-known evolutionarily conserved transcriptional factor, which plays critical roles in many biological processes including inflammation, immunity, cell proliferation, survival and apoptosis through regulating related target genes expression. The activation of NF-κB, which is rigorously controlled in vivo, is essential for cellular physiological function. Once this activity is disturbed, many diseases, including cancer, arthrositis, periodontitis and bone degradaton are followed. Therefore, NF-κB has become a promising drug target for these diseases.
The activation of NF-κB is a multiple steps progress, including IκBαphosphorylation and degradation, nuclear translocation of NF-κB subunits, binding with specific DNA sequences and finally regulating its target genes expression. According to these steps, we firstly established a systemic assays model to evaluate the activity of NF-κB. Secondly, we found some inhibitors of NF-κB signaling pathway by screening small molecular compounds, which come from traditional Chinese medicine(TCM) using these assay models. We then studied one of these active compounds, maslinic acid (MA), and discovered the functions of MA in cancer and osteoclastogenesis and also elucidated the exact mechanisms involved in these physiological functions.
In this study, we firstly studied the antitumor effects of MA in pancreatic cancer, and we found the following results:
1 MA could enhance TNFα-induced pancreatic cancer cell growth;
2 MA could potentiates TNFα-induced pancreatic cancer cell apoptosis;
3 MA could activate caspase-dependent apoptotic pathway;
4 MA could inhibit TNFα-induced pancreatic cancer cell migration;
5 MA blocked TNFα-induced NF-κB activation and genes expression;
6 MA suppressed pancreatic tumor growth and induced apoptosis in vivo.
Together, in this part of our study, for the first time, our results showed that MA can enhance the anti-tumor activities of TNFa and inhibit pancreatic tumor growth and invasion by activating caspase-dependent apoptotic pathway and by suppressing NF-κB activation and- its downstream genes expression. Therefore, we concluded that MA together with TNFa could be new promising agents in the treatment of pancreatic cancer.
We next determined the effects of MA on osteoclast differentiation and functions. And we observed the following phenomena:
1 MA suppressed osteoclast differentiation and these suppressions were only observed at early stage during ostoclastogenesis;
2 MA had little effects on precursors of osteoclast when treated with the lower concentration used in differentiation assay;
3 MA blocked RANKL-induced actin-ring formation;
4 MA inhibited RANKL-induced bone resorption on spicula in pits assay;
5 MA ameliorated ovariectomy-induced bone loss in vivo;
We further studied the molecular mechanisms of these observations. And we found that:
1 MA blocked NF-κB and MAPK-AP1 activation;
2 MA suppressed NFAT-c1 expression but not its activation;
3 MA down regulated some osteoclast related genes expression;
4 Maslinic acid cannot break RANKL induced calcium signaling in RAW264.7 cells.
Taken together, in this part of our study, our results firstly demonstrated that MA could suppress RANKL-induced osteoclastogenesis and function through suppression NF-κB and MAPKs/AP-1 signaling pathway. These results suggested that MA could be a new promising agent in the treatment of osteoclast related diseases such as osteoporosis.
Taken all together, we discovered some novel inhibitors of NF-κB signaling pathway using a systemic study platform for NF-κB signaling pathway we established in our lab. Furthermore, we also studied the effects of maslinic acid (MA), one of our discovered active compounds from TCM, on its antitumor and antiosteoclastogenic activities in vitro and in vivo. We found that MA could potentiate TNFα-induced pancreatic cancer cell apoptosis and suppress RANKL-induced osteoclastogenesis by regulating NF-κB signaling pathway. These results supported that MA could be a new promising agent both in the treatment of cancer and osteoclast related diseases such as osteoporosis.
NF-κB的活化是一个多步骤的过程,当激活因子从细胞表面进入细胞内后,首先激活上游激酶(IKK),再通过激酶磷酸化NF-κB的抑制亚单位IκBα,进而导致NF-κB从细胞质进入到细胞核,与特定的靶标结合,调控相关基因表达,最后调控相关的生理过程。根据NF-κB这些特点,本课题进行了以下方面的研究：
一、建立了NF-κB活性的各种检测方法,包括：NF-κB报告基因分析方法,免疫荧光的方法(检测NF-κB在细胞内的定位),电泳迁移率实验(EMSA-electrophoretic mobility shift assay),蛋白印迹的方法(分析抑制亚单位IκBα的降解情况和调控基因表达情况)和染色质免疫共沉淀的方法(chromatin immunoprecipitation assay, ChIP)来研究分析NF-κB对疾病的调控作用和筛选发现调控NF-κB活性的药物。另一方面,我们还建立了包括裸鼠荷瘤,肿瘤转移和骨质疏松的动物模型,以期望进一步在体内对NF-κB进行机理和应用方面的深入研究。
二、利用建好的NF-κB实验模型,我们筛选得到了数个NF-κB信号通路的抑制剂,并选取了其中一个活性小分子——山楂酸,进一步对山楂酸在抗肿瘤方面的机理进行了研究。我们研究发现：
1、山楂酸具有抑制胰腺癌细胞增值的作用。在TNFα存在时,这种抑制效果更加明显,统计表明显著增强；
2、山楂酸与TNFα协同抑制胰腺癌细胞增殖的作用,是通过促进细胞凋亡来实现的；
3、山楂酸是通过抑制NF-κB的活化来促进胰腺癌细胞凋亡的；
4、在体外,山楂酸处理能够抑制NF-κB下游的相关基因的表达；
5、裸鼠体内实验进一步证明山楂酸处理能够抑制胰腺癌肿瘤的生长,促进胰腺肿瘤细胞凋亡。
这些结果提示山楂酸处理能够分别在体内和体外抑制肿瘤细胞的生长,他的抗癌机理是通过抑制NF-κB信号通路的活化和NF-κB下游相关基因的表达来实现的,这就提示,山楂酸和TNFα一起联合使用可能对胰腺癌的治疗有所帮助。
三、我们课题的另外一个部分研究发现山楂酸能够抑制破骨细胞的分化和功能。这些研究结果包括：
1、研究发现山楂酸能够抑制破骨细胞分化,而且具有时间和浓度剂量依赖性；
2、山楂酸还能够抑制破骨细胞特殊的功能结构肌动蛋白环(ACTIN-RING)的形成；
3、pits assay证实,在体外山楂酸能够抑制破骨细胞对骨片的吸收；4、在体内,我们进一步发现,山楂酸能够抑制由于卵巢切除导致的小鼠骨质流失；
5、进一步研究表明,山楂酸能够抑制由于卵巢切除导致的破骨细胞活性升高。
这些现象提示,山楂酸能够抑制破骨细胞的分化和功能,而且对卵巢切除导致的骨质疏松有预防和治疗作用。我们进一步探讨了这些现象的机理。研究发现：
1、山楂酸处理能够抑制RANKL诱导引起的NF-κB信号通路的活化；
2、山楂酸处理能够抑制RANKL诱导的引起的MAPK-AP1信号通路的活化；
3、山楂酸处理能够抑制NFAT-c1的表达,但是不影响其活性；
4、山楂酸处理能够抑制破骨细胞分化和功能相关基因的表达；
5、山楂酸处理不影响RANKL诱发的细胞内钙流水平；
通过上述研究,我们初步证明了山楂酸能够通过抑制NF-κB信号通路和MAPK-AP1信号通路的活化来抑制破骨细胞的分化和功能,而且我们在动物水平验证了山楂酸能够抑制由于激素水平下降导致的骨质流失,这些结果为山楂酸在预防和治疗破骨细胞相关疾病如骨质疏松症方面提供了理论支持。
综上所述,我们成功的建立了在分子、细胞和动物水平的NF-κB信号通路研究模型,为下一步进行跟NF-κB信号通路相关的机理研究和运用研究奠定了基础。利用建立的模型,我们筛选获得了数个NF-κB信号通路的小分子抑制剂。紧接着,我们对其中之一的山楂酸的功能和机理进行了深入研究。我们发现：山楂酸和肿瘤坏死因子α联合使用具有良好的抗肿瘤效果。而且我们的研究还发现,山楂酸能够抑制破骨前体细胞的分化和功能,在体内能够抑制由于卵巢切除导致的骨质疏松。这些研究为以后山楂酸在肿瘤治疗,破骨细胞相关疾病的预防和治疗方面提供了理论支持。同时,我们的这部分研究也为以后利用NF-κB信号通路研究模型提供了有益探索和尝试。
Abstract
Nuclear Factor-KB (NF-κB), an well-known evolutionarily conserved transcriptional factor, which plays critical roles in many biological processes including inflammation, immunity, cell proliferation, survival and apoptosis through regulating related target genes expression. The activation of NF-κB, which is rigorously controlled in vivo, is essential for cellular physiological function. Once this activity is disturbed, many diseases, including cancer, arthrositis, periodontitis and bone degradaton are followed. Therefore, NF-κB has become a promising drug target for these diseases.
The activation of NF-κB is a multiple steps progress, including IκBαphosphorylation and degradation, nuclear translocation of NF-κB subunits, binding with specific DNA sequences and finally regulating its target genes expression. According to these steps, we firstly established a systemic assays model to evaluate the activity of NF-κB. Secondly, we found some inhibitors of NF-κB signaling pathway by screening small molecular compounds, which come from traditional Chinese medicine(TCM) using these assay models. We then studied one of these active compounds, maslinic acid (MA), and discovered the functions of MA in cancer and osteoclastogenesis and also elucidated the exact mechanisms involved in these physiological functions.
In this study, we firstly studied the antitumor effects of MA in pancreatic cancer, and we found the following results:
1 MA could enhance TNFα-induced pancreatic cancer cell growth;
2 MA could potentiates TNFα-induced pancreatic cancer cell apoptosis;
3 MA could activate caspase-dependent apoptotic pathway;
4 MA could inhibit TNFα-induced pancreatic cancer cell migration;
5 MA blocked TNFα-induced NF-κB activation and genes expression;
6 MA suppressed pancreatic tumor growth and induced apoptosis in vivo.
Together, in this part of our study, for the first time, our results showed that MA can enhance the anti-tumor activities of TNFa and inhibit pancreatic tumor growth and invasion by activating caspase-dependent apoptotic pathway and by suppressing NF-κB activation and- its downstream genes expression. Therefore, we concluded that MA together with TNFa could be new promising agents in the treatment of pancreatic cancer.
We next determined the effects of MA on osteoclast differentiation and functions. And we observed the following phenomena:
1 MA suppressed osteoclast differentiation and these suppressions were only observed at early stage during ostoclastogenesis;
2 MA had little effects on precursors of osteoclast when treated with the lower concentration used in differentiation assay;
3 MA blocked RANKL-induced actin-ring formation;
4 MA inhibited RANKL-induced bone resorption on spicula in pits assay;
5 MA ameliorated ovariectomy-induced bone loss in vivo;
We further studied the molecular mechanisms of these observations. And we found that:
1 MA blocked NF-κB and MAPK-AP1 activation;
2 MA suppressed NFAT-c1 expression but not its activation;
3 MA down regulated some osteoclast related genes expression;
4 Maslinic acid cannot break RANKL induced calcium signaling in RAW264.7 cells.
Taken together, in this part of our study, our results firstly demonstrated that MA could suppress RANKL-induced osteoclastogenesis and function through suppression NF-κB and MAPKs/AP-1 signaling pathway. These results suggested that MA could be a new promising agent in the treatment of osteoclast related diseases such as osteoporosis.
Taken all together, we discovered some novel inhibitors of NF-κB signaling pathway using a systemic study platform for NF-κB signaling pathway we established in our lab. Furthermore, we also studied the effects of maslinic acid (MA), one of our discovered active compounds from TCM, on its antitumor and antiosteoclastogenic activities in vitro and in vivo. We found that MA could potentiate TNFα-induced pancreatic cancer cell apoptosis and suppress RANKL-induced osteoclastogenesis by regulating NF-κB signaling pathway. These results supported that MA could be a new promising agent both in the treatment of cancer and osteoclast related diseases such as osteoporosis.
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