ROS/AMPK介导的凋亡通路在川芎嗪抗胃癌作用中的机制研究
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摘要
胃癌是消化系统最为常见的恶性肿瘤,整体预后不佳,化疗是其主要治疗手段之一。但是,现有的化疗药物存在着副作用大、化疗耐药等诸多问题,因此,从天然药物中寻找有效的胃癌辅助治疗药物,可为胃癌治疗提供新的途径。川芎嗪(Tetramethylpyrazine, TMPZ)是从川芎中提取的一种生物碱单体,其传统治疗作用主要表现为改善微循环、抗氧化应激方面。近些年来,川芎嗪在抗肿瘤治疗方面逐渐成为国内学者研究的热点,并有研究指出川芎嗪能逆转胃癌细胞多药耐药,但是,川芎嗪是否本身有抗胃癌作用,其机制又是什么,迄今为止,并无研究报道。
AMP激活的蛋白激酶(AMP-activated protein kinase, AMPK)是细胞内的“能量调节器”,AMPK在能量缺乏时被激活,能量过量时抑制,其激活后能抑制细胞内蛋白质、脂肪酸、多糖的合成,这些过程为肿瘤细胞增殖、发展所必须。并且我们在对临床标本的检测中发现,AMPK的活性状态磷酸化AMPK (phosph-AMPK)的表达在胃癌组织中几乎检测不到或仅微弱表达。那么,川芎嗪是否可以通过激活AMPK来达到抑制胃癌生长的目的呢?目前为止,尚无任何文献报道。
本课题以SGC7901胃癌细胞为研究对象,研究TMPZ在不同药物浓度、不同时间点对SGC7901胃癌细胞生长情况、凋亡的影响。在明确TMPZ可抑制胃癌细胞生长、促进细胞凋亡的基础上,从ROS/AMPK信号通路途径对TMPZ抗胃癌作用机制进行探讨,现将本论文主要研究结果归纳如下：
1,收集病理确认的胃癌组织、癌旁组织和正常胃黏膜组织,免疫组化检测磷酸化AMPK (p-AMPK)的表达情况。结果显示,p-AMPK在正常组织中94%阳性表达,其阳性表达率高于癌旁组织72%(36/50)及胃癌组织4%(2/50),而癌旁组织中p-AMPK蛋白表达显著高于胃癌组织。进一步的Western blot结果显示p-AMPK蛋白表达量在正常组织为0.93±0.14、癌旁组织为0.43±0.08,胃癌组织为0.07±0.01,差异有显著性(P<0.05)
2.探讨了TMPZ对SGC7901胃癌细胞的量效、时效关系。以不同浓度梯度的TMPZ (0,0.5,1,2,4,6,8mM)处理6,12,24,48h以后,噻唑蓝(MTT)比色法观察SGC7901细胞的生长情况。不同浓度梯度的TMPZ作用于SGC7901胃癌细胞24h后,流式细胞仪检测细胞凋亡情况。结果发现,低浓度的TMPZ对胃癌细胞生长无明显影响,较高浓度的TMPZ(4,6,8mM)在24h开始明显抑制胃癌细胞生长；并且,在TMPZ处理24h后明显诱导肿瘤细胞的凋亡,其作用呈一定的浓度依赖性；同时我们进一步证实,较高浓度的TMPZ对人胃黏膜上皮细胞GES-1、人脐静脉内皮细胞HUVECs、心肌样细胞H9c2的细胞凋亡并不产生明显影响；
3.针对高浓度的TMPZ呈剂量依赖性地诱导肿瘤细胞凋亡,流式细胞仪检测高浓度TMPZ对ROS生成的影响,结果发现,高浓度的TMPZ呈浓度依赖性地升高肿瘤细胞ROS的含量,并且抑制细胞生长；给予ROS清除剂N-乙酰半胱氨酸(NAC)之后,ROS含量明显下降,并且高浓度的TMPZ不再能抑制肿瘤细胞的生长；
4. Western blot法检测高浓度的TMPZ对胃癌SGC7901细胞AMPK磷酸化激活的影响。结果发现高浓度的TMPZ呈剂量依赖性地激活AMPK,使AMPK磷酸化水平增多,但是给予NAC之后,高浓度TMPZ所诱导的AMPK的磷酸化激活被取消；
5.使用AMPK特异性的阻断剂Compound C,深入探讨高浓度TMPZ通过ROS/AMPK信号通路介导通过线粒体凋亡途径。结果表明,TMPZ通过激活AMPK,促使Bax从胞浆向线粒体迁移,使线粒体膜电位崩解,细胞色素C (cytochromec,Cyt c)从线粒体释放至胞浆中,然后激活caspase-9、caspase-3,从而导致胃癌SGC7901细胞凋亡。
综上所述,从临床胃癌组织标本中AMPK活性被显著抑制这一现象得到启发,对TMPZ抗胃癌细胞SGC7901作用及机制进行研究发现：TMPZ高浓度抑制胃癌细胞生长,促进胃癌细胞凋亡,但并不会对其它细胞产生明显的影响。其机制可能是高浓度TMPZ诱导产生大量ROS,从而激活AMPK,促使Bax从胞浆迁移至线粒体,导致线粒体膜电位崩解,Cyt c释放至胞浆,激活caspase-9、caspase-3,最终导致肿瘤细胞凋亡。
Gastric cancer is the most common malignant tumor of digestive system with a poor overall prognosis, and chemotherapy is the main treatment method. However, existing chemotherapeutic agents have side effects, drug resistance and many other issues.To find effective drug for treating gastric cancer from natural drugs can provide a new approach for the treatment of gastric cancer. Tetramethylpyrazine (Tetramethylpyrazine, TMPZ) is an alkaloid extracted from the rhizome of chuanxiong whose traditional treatment effect is mainly manifested as improving microcirculation, anti-oxidative stress. In recent years, tetramethylpyrazine has become the focus in anti-tumor therapy research, and studies have shown that tetramethylpyrazine can reverse multiple drug resistance(MDR) in gastric cancer. However,whether tetramethylpyrazine itself has anti tumor effect and what is the mechanism, there is no relevant research reports so far.
AMP activated protein kinase (AMPK AMP-activated protein kinase,) is an intracellular "energy regulator", which was activated when cell was in the energy shortage condition and was inhibited in energy excess condition. While the activation of AMPK can inhibit the synthesis of intracellular protein, fatty acid, polysaccharide, and the process is necessary for tumor cell proliferation and development. Previously we have found in the clinical samples that the expression of activity status of AMPK-phosphorylation status of AMPK (phosph-AMPK) in gastric cancer tissues were almost undetectable or very weak. Whether tetramethylpyrazine could inhibit the growth of gastric cancer through the activation of AMPK? So far, there is no report in the literature.
This study foused on the research of the effection on gastric cancer cell growth and apoptosis of different concentrations of TMPZ,on different time points by using gastric cancer cell SGC7901as the research object. On the base of that TMPZ could inhibit the growth of gastric cancer cells and promote it's apoptosis,we further explored the mechanism of TMPZ's anti gastric cancer effect from the ROS/AMPK signal pathway, and the main results in this dissertation were summarized as follows:
1. Expression of phosphorylated AMPK in pathologically confirmed gastric cancer tissues, paracancerous tissues and normal gastric mucosa tissue were detected using immunohistochemistry.The results showed that, the positive expression of phosph-AMPK was94.0%in normal gastric mucosa tissues, in paracancerous tissues was72.0%, and in carcinoma there was4.0%almost no expression. The expression of p-AMPK protein in normal gastric mucosa tissues was significantly higher than that in paracancerous tissues and gastric cancer tissues,while the expression of p-AMPK protein in paracancerous tissues was significantly higher than that in gastric cancer tissues.Further Western blot analysis showed that p-AMPK protein expression in normal tissues was0.93±0.14, in paracancerous tissues was0.43±0.08and in gastric cancer tissues was0.07±0.01, there was significant difference between the three group(P<0.05).
2.Investigation of the effects of TMPZ on human gastric cancer cell SGC7901and the dose-effect, time-effect relationship. We treated the tumor cells with different concentrations of TMPZ (0,0.5,1,2,4,6,8mM) for6,12,24,48h, and methyl thiazolyl tetrazolium (MTT) assay was used to examine the growth of the tumor cells. Different concentrations of TMPZ treatment of the tumor cells for24h, cell apoptosis was detected by flow cytometry. The results showed that there was no significant effect of low concentration TMPZ on the growth of the tumor cells, while high concentration TMPZ (4,6,8mM) significantly inhibited the growth of the tumor cells after24h; and obviously induced the apoptosis of the tumor cells after24h treatment in a concentration-dependent manner. At the same time, we further confirmed that higher concentrations TMPZ had no significant effect on the survival rate and the apoptosis of human gastric epithelial cells GES-1, human umbilical vein endothelial cells HUVECs and human Myocardial cells H9c2.
3.According to the apoptosis of tumor cells induced by the high concentration TMPZ in a dose-dependent manner, we used flow cytometry to detect how the high concentration of TMPZ effceted the ROS production and we found that the high concentration TMPZ could raise the concentration of ROS in tumor cells in a dose-dependent manner and inhibit the tumor cells growth. After administration of NAC,a ROS scavenger, ROS content in cells decreased significantly, and the high concentration TMPZ could not inhibit the growth of tumor cells anymore.
4.Western blot detection the effect of high concentration TMPZ in phosphorylation of AMPK in human gastric cancer cell line SGC7901. Results showed that the high concentration TMPZ could activate AMPK in a dose-dependent manner and increase the phosphorylation level of AMPK, but after administration of NAC, phosphorylation of AMPK induced by high concentration TMPZ was abolished.
5.Using AMPK specific inhibitor Compound C, we deeply study the high concentration TMPZ activation the mitochondrial apoptosis pathway through the ROS/AMPK signaling pathway. The results showed that, through the activation of AMPK,TMPZ promoted the migration of Bax from the cytosol to the mitochondria, and the collapse of mitochondrial membrane potential, then cytochrome C released from mitochondria to cytosol, and activated caspase-9, Caspase-3, resulting in apoptosis of gastric cancer cell line SGC7901.
To sum up, inspired by the AMPK activity in gastric cancer tissues,we studied the effect of TMPZ against gastric cancer cell SGC7901and it's mechanism.We found that high concentration TMPZ inhibited the growth of gastric cancer cells, and promoted the apoptosis of gastric cancer cells, but did not have significant effect on the other cells. The mechanism may be that the high concentration TMPZ induced the generatin of a large amount of ROS, leading to activation of AMPK, Bax migration from the cytosol to the mitochondria, leading to mitochondrial membrane potential collapse, then CytC was released into the cytoplasm, to activate caspase-9, caspase-3. finally induce the apoptosis of tumor cells.
AMP激活的蛋白激酶(AMP-activated protein kinase, AMPK)是细胞内的“能量调节器”,AMPK在能量缺乏时被激活,能量过量时抑制,其激活后能抑制细胞内蛋白质、脂肪酸、多糖的合成,这些过程为肿瘤细胞增殖、发展所必须。并且我们在对临床标本的检测中发现,AMPK的活性状态磷酸化AMPK (phosph-AMPK)的表达在胃癌组织中几乎检测不到或仅微弱表达。那么,川芎嗪是否可以通过激活AMPK来达到抑制胃癌生长的目的呢?目前为止,尚无任何文献报道。
本课题以SGC7901胃癌细胞为研究对象,研究TMPZ在不同药物浓度、不同时间点对SGC7901胃癌细胞生长情况、凋亡的影响。在明确TMPZ可抑制胃癌细胞生长、促进细胞凋亡的基础上,从ROS/AMPK信号通路途径对TMPZ抗胃癌作用机制进行探讨,现将本论文主要研究结果归纳如下：
1,收集病理确认的胃癌组织、癌旁组织和正常胃黏膜组织,免疫组化检测磷酸化AMPK (p-AMPK)的表达情况。结果显示,p-AMPK在正常组织中94%阳性表达,其阳性表达率高于癌旁组织72%(36/50)及胃癌组织4%(2/50),而癌旁组织中p-AMPK蛋白表达显著高于胃癌组织。进一步的Western blot结果显示p-AMPK蛋白表达量在正常组织为0.93±0.14、癌旁组织为0.43±0.08,胃癌组织为0.07±0.01,差异有显著性(P<0.05)
2.探讨了TMPZ对SGC7901胃癌细胞的量效、时效关系。以不同浓度梯度的TMPZ (0,0.5,1,2,4,6,8mM)处理6,12,24,48h以后,噻唑蓝(MTT)比色法观察SGC7901细胞的生长情况。不同浓度梯度的TMPZ作用于SGC7901胃癌细胞24h后,流式细胞仪检测细胞凋亡情况。结果发现,低浓度的TMPZ对胃癌细胞生长无明显影响,较高浓度的TMPZ(4,6,8mM)在24h开始明显抑制胃癌细胞生长；并且,在TMPZ处理24h后明显诱导肿瘤细胞的凋亡,其作用呈一定的浓度依赖性；同时我们进一步证实,较高浓度的TMPZ对人胃黏膜上皮细胞GES-1、人脐静脉内皮细胞HUVECs、心肌样细胞H9c2的细胞凋亡并不产生明显影响；
3.针对高浓度的TMPZ呈剂量依赖性地诱导肿瘤细胞凋亡,流式细胞仪检测高浓度TMPZ对ROS生成的影响,结果发现,高浓度的TMPZ呈浓度依赖性地升高肿瘤细胞ROS的含量,并且抑制细胞生长；给予ROS清除剂N-乙酰半胱氨酸(NAC)之后,ROS含量明显下降,并且高浓度的TMPZ不再能抑制肿瘤细胞的生长；
4. Western blot法检测高浓度的TMPZ对胃癌SGC7901细胞AMPK磷酸化激活的影响。结果发现高浓度的TMPZ呈剂量依赖性地激活AMPK,使AMPK磷酸化水平增多,但是给予NAC之后,高浓度TMPZ所诱导的AMPK的磷酸化激活被取消；
5.使用AMPK特异性的阻断剂Compound C,深入探讨高浓度TMPZ通过ROS/AMPK信号通路介导通过线粒体凋亡途径。结果表明,TMPZ通过激活AMPK,促使Bax从胞浆向线粒体迁移,使线粒体膜电位崩解,细胞色素C (cytochromec,Cyt c)从线粒体释放至胞浆中,然后激活caspase-9、caspase-3,从而导致胃癌SGC7901细胞凋亡。
综上所述,从临床胃癌组织标本中AMPK活性被显著抑制这一现象得到启发,对TMPZ抗胃癌细胞SGC7901作用及机制进行研究发现：TMPZ高浓度抑制胃癌细胞生长,促进胃癌细胞凋亡,但并不会对其它细胞产生明显的影响。其机制可能是高浓度TMPZ诱导产生大量ROS,从而激活AMPK,促使Bax从胞浆迁移至线粒体,导致线粒体膜电位崩解,Cyt c释放至胞浆,激活caspase-9、caspase-3,最终导致肿瘤细胞凋亡。
Gastric cancer is the most common malignant tumor of digestive system with a poor overall prognosis, and chemotherapy is the main treatment method. However, existing chemotherapeutic agents have side effects, drug resistance and many other issues.To find effective drug for treating gastric cancer from natural drugs can provide a new approach for the treatment of gastric cancer. Tetramethylpyrazine (Tetramethylpyrazine, TMPZ) is an alkaloid extracted from the rhizome of chuanxiong whose traditional treatment effect is mainly manifested as improving microcirculation, anti-oxidative stress. In recent years, tetramethylpyrazine has become the focus in anti-tumor therapy research, and studies have shown that tetramethylpyrazine can reverse multiple drug resistance(MDR) in gastric cancer. However,whether tetramethylpyrazine itself has anti tumor effect and what is the mechanism, there is no relevant research reports so far.
AMP activated protein kinase (AMPK AMP-activated protein kinase,) is an intracellular "energy regulator", which was activated when cell was in the energy shortage condition and was inhibited in energy excess condition. While the activation of AMPK can inhibit the synthesis of intracellular protein, fatty acid, polysaccharide, and the process is necessary for tumor cell proliferation and development. Previously we have found in the clinical samples that the expression of activity status of AMPK-phosphorylation status of AMPK (phosph-AMPK) in gastric cancer tissues were almost undetectable or very weak. Whether tetramethylpyrazine could inhibit the growth of gastric cancer through the activation of AMPK? So far, there is no report in the literature.
This study foused on the research of the effection on gastric cancer cell growth and apoptosis of different concentrations of TMPZ,on different time points by using gastric cancer cell SGC7901as the research object. On the base of that TMPZ could inhibit the growth of gastric cancer cells and promote it's apoptosis,we further explored the mechanism of TMPZ's anti gastric cancer effect from the ROS/AMPK signal pathway, and the main results in this dissertation were summarized as follows:
1. Expression of phosphorylated AMPK in pathologically confirmed gastric cancer tissues, paracancerous tissues and normal gastric mucosa tissue were detected using immunohistochemistry.The results showed that, the positive expression of phosph-AMPK was94.0%in normal gastric mucosa tissues, in paracancerous tissues was72.0%, and in carcinoma there was4.0%almost no expression. The expression of p-AMPK protein in normal gastric mucosa tissues was significantly higher than that in paracancerous tissues and gastric cancer tissues,while the expression of p-AMPK protein in paracancerous tissues was significantly higher than that in gastric cancer tissues.Further Western blot analysis showed that p-AMPK protein expression in normal tissues was0.93±0.14, in paracancerous tissues was0.43±0.08and in gastric cancer tissues was0.07±0.01, there was significant difference between the three group(P<0.05).
2.Investigation of the effects of TMPZ on human gastric cancer cell SGC7901and the dose-effect, time-effect relationship. We treated the tumor cells with different concentrations of TMPZ (0,0.5,1,2,4,6,8mM) for6,12,24,48h, and methyl thiazolyl tetrazolium (MTT) assay was used to examine the growth of the tumor cells. Different concentrations of TMPZ treatment of the tumor cells for24h, cell apoptosis was detected by flow cytometry. The results showed that there was no significant effect of low concentration TMPZ on the growth of the tumor cells, while high concentration TMPZ (4,6,8mM) significantly inhibited the growth of the tumor cells after24h; and obviously induced the apoptosis of the tumor cells after24h treatment in a concentration-dependent manner. At the same time, we further confirmed that higher concentrations TMPZ had no significant effect on the survival rate and the apoptosis of human gastric epithelial cells GES-1, human umbilical vein endothelial cells HUVECs and human Myocardial cells H9c2.
3.According to the apoptosis of tumor cells induced by the high concentration TMPZ in a dose-dependent manner, we used flow cytometry to detect how the high concentration of TMPZ effceted the ROS production and we found that the high concentration TMPZ could raise the concentration of ROS in tumor cells in a dose-dependent manner and inhibit the tumor cells growth. After administration of NAC,a ROS scavenger, ROS content in cells decreased significantly, and the high concentration TMPZ could not inhibit the growth of tumor cells anymore.
4.Western blot detection the effect of high concentration TMPZ in phosphorylation of AMPK in human gastric cancer cell line SGC7901. Results showed that the high concentration TMPZ could activate AMPK in a dose-dependent manner and increase the phosphorylation level of AMPK, but after administration of NAC, phosphorylation of AMPK induced by high concentration TMPZ was abolished.
5.Using AMPK specific inhibitor Compound C, we deeply study the high concentration TMPZ activation the mitochondrial apoptosis pathway through the ROS/AMPK signaling pathway. The results showed that, through the activation of AMPK,TMPZ promoted the migration of Bax from the cytosol to the mitochondria, and the collapse of mitochondrial membrane potential, then cytochrome C released from mitochondria to cytosol, and activated caspase-9, Caspase-3, resulting in apoptosis of gastric cancer cell line SGC7901.
To sum up, inspired by the AMPK activity in gastric cancer tissues,we studied the effect of TMPZ against gastric cancer cell SGC7901and it's mechanism.We found that high concentration TMPZ inhibited the growth of gastric cancer cells, and promoted the apoptosis of gastric cancer cells, but did not have significant effect on the other cells. The mechanism may be that the high concentration TMPZ induced the generatin of a large amount of ROS, leading to activation of AMPK, Bax migration from the cytosol to the mitochondria, leading to mitochondrial membrane potential collapse, then CytC was released into the cytoplasm, to activate caspase-9, caspase-3. finally induce the apoptosis of tumor cells.
引文
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