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二甲双胍通过AMPK途径增强肝癌细胞对顺铂的化疗敏感性。

Metformin enhances the chemosensitivity of hepatocarcinoma cells to cisplatin through AMPK pathway.

作者信息

Dong Hao, Huang Jungang, Zheng Kang, Tan Dong, Chang Qi, Gong Genqiang, Zhang Qing, Tang Hanqiu, Sun Jianguo, Zhang Shaoyu

机构信息

Department of Hepatobiliary Surgery, The Central Hospital of Xianyang, Xianyang, Shaanxi, P.R. China.

Department of General Surgery, Traditional Chinese Medicine Hospital of Hanzhong, Hanzhong, Shaanxi, P.R. China.

出版信息

Oncol Lett. 2017 Dec;14(6):7807-7812. doi: 10.3892/ol.2017.7198. Epub 2017 Oct 17.

DOI:10.3892/ol.2017.7198
PMID:29344225
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5755027/
Abstract

This study investigated the effect of metformin on chemosensitivity of hepatocarcinoma cells to cisplatin and the possible mechanism. HepG2 and Huh-7 hepatoma cells were treated with cisplatin at concentrations of 0, 2, 4, 6, 8 and 10 µM for 48 h. Proliferation of HepG2 and Huh-7 hepatoma cells were detected by MTT assay. Apoptosis of hepatocellular carcinoma cells was detected by flow cytometry. Western blot analysis was used to detect the expression of 5-monophosphate-activated protein kinase (AMPK) and p-AMPK protein. Proliferative activity of HepG2 and Huh-7 cells decreased with the increase of cisplatin concentration. After adding metformin, proliferation ability of hepatocarcinoma cells was significantly reduced. Apoptosis rate of the metformin was significantly higher than that of the control group, and apoptosis rate of the cisplatin + metformin was significantly higher than that of the cisplatin group. There was no significant difference in expression level of AMPK protein found between control, metformin, cisplatin and cisplatin + metformin group. Compared with the control, ratio of p-AMPK/AMPK in metformin group was increased, and ratio of p-AMPK/AMPK in cisplatin + metformin was significantly higher than that in cisplatin group. Activity of cells in cisplatin + metformin + compound C (AMPK pathway blocker) group was significantly higher than that of cisplatin + metformin, while apoptosis of cells in cisplatin + metformin + compound C (AMPK pathway blocker) was significantly lower than that of cisplatin + metformin group. In conclusion, metformin can inhibit the proliferation, promote apoptosis and enhance the chemosensitivity of hepatocarcinoma cells to cisplatin through AMPK pathway.

摘要

本研究探讨了二甲双胍对肝癌细胞对顺铂化疗敏感性的影响及其可能机制。将HepG2和Huh-7肝癌细胞分别用浓度为0、2、4、6、8和10 μM的顺铂处理48小时。采用MTT法检测HepG2和Huh-7肝癌细胞的增殖情况。通过流式细胞术检测肝癌细胞的凋亡情况。采用蛋白质免疫印迹法检测5-单磷酸腺苷激活蛋白激酶（AMPK）和磷酸化AMPK（p-AMPK）蛋白的表达。HepG2和Huh-7细胞的增殖活性随顺铂浓度的增加而降低。加入二甲双胍后，肝癌细胞的增殖能力显著降低。二甲双胍组的凋亡率显著高于对照组，顺铂+二甲双胍组的凋亡率显著高于顺铂组。对照组、二甲双胍组、顺铂组和顺铂+二甲双胍组之间AMPK蛋白表达水平无显著差异。与对照组相比，二甲双胍组p-AMPK/AMPK比值升高，顺铂+二甲双胍组p-AMPK/AMPK比值显著高于顺铂组。顺铂+二甲双胍+化合物C（AMPK通路阻滞剂）组细胞活性显著高于顺铂+二甲双胍组，而顺铂+二甲双胍+化合物C（AMPK通路阻滞剂）组细胞凋亡率显著低于顺铂+二甲双胍组。综上所述，二甲双胍可通过AMPK通路抑制肝癌细胞增殖、促进凋亡并增强其对顺铂的化疗敏感性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10bb/5755027/5e8db4035438/ol-14-06-7807-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10bb/5755027/9ebab438cc1f/ol-14-06-7807-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10bb/5755027/613e9771e5ea/ol-14-06-7807-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10bb/5755027/28c629722a03/ol-14-06-7807-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10bb/5755027/5e8db4035438/ol-14-06-7807-g03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10bb/5755027/9ebab438cc1f/ol-14-06-7807-g00.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10bb/5755027/613e9771e5ea/ol-14-06-7807-g01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10bb/5755027/28c629722a03/ol-14-06-7807-g02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/10bb/5755027/5e8db4035438/ol-14-06-7807-g03.jpg

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