Metformin inhibits the invasion of human hepatocellular carcinoma cells and enhances the chemosensitivity to sorafenib through a downregulation of the ERK/JNK-mediated NF-κB-dependent pathway that reduces uPA and MMP-9 expression
Metformin inhibits the invasion of human hepatocellular carcinoma cells and enhances the chemosensitivity to sorafenib through a downregulation of the ERK/JNK-mediated NF-κB-dependent pathway that reduces uPA and MMP-9 expression
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DOI：
10.1007/s00726-014-1838-4
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发表时间：
2014-12-01
期刊：
影响因子：
3.5
通讯作者：
Hsieh, Yi-Hsien
中科院分区：
文献类型：
--
作者：
Hsieh, Shu-Ching;Tsai, Jen-Pi;Hsieh, Yi-Hsien
二甲双胍已在几种癌细胞和动物模型中显示出抗癌活性。然而，其抗转移活性的分子机制仍然知之甚少，需要进一步研究。本研究的目的是评估二甲双胍抑制肝细胞癌（HCC）细胞迁移和侵袭的能力，并确定其对信号通路的影响。我们的数据表明，二甲双胍抑制人类HCC细胞的迁移和侵袭。二甲双胍还能显著抑制肝癌细胞中MMP-9和uPA的表达和分泌，抑制ERK1/2和JNK1/2的磷酸化。ERK1/2抑制剂（PD98059）或JNK1/2抑制剂（SP600125）可增强二甲双胍对HCC细胞迁移和侵袭的抑制作用。此外，二甲双胍诱导的MMP-9和uPA启动子活性的抑制也阻断了NF-kappa B的核易位及其与MMP-9和uPA启动子的结合，PD98059或SP600125进一步增强了这些抑制作用。此外，二甲双胍显著增强了索拉非尼的抗转移作用。综上所述，二甲双胍通过抑制ERK/ jnk介导的NF-kappa b依赖通路，从而降低uPA和MMP-9的表达，从而抑制HCC细胞的迁移和侵袭。此外，二甲双胍和索拉非尼联合治疗在抑制细胞迁移和肝癌细胞侵袭方面具有协同抑制作用。这些发现提供了二甲双胍抗转移作用的分子机制，以及其增强HCC细胞对索拉非尼的化学敏感性的能力。
Metformin has been shown to exert anti-cancer activities in several cancer cells and animal models. However, the molecular mechanisms of its anti-metastatic activities remain poorly understood and warrant further investigation. The aims of this study were to evaluate the ability of metformin to inhibit the migration and invasion of hepatocellular carcinoma (HCC) cells and identify its effects on signaling pathways. Our data indicate that metformin inhibits the migration and invasion of human HCC cells. Metformin was also found to significantly inhibit the expression and secretion of MMP-9 and uPA in HCC cells, and suppress the phosphorylation of ERK1/2 and JNK1/2. Treatment with an ERK1/2 inhibitor (PD98059) or JNK1/2 inhibitor (SP600125) enhanced the inhibitory effects of metformin on the migration and invasion of HCC cells. Moreover, metformin-induced inhibition of MMP-9 and uPA promoter activity also blocked the nuclear translocation of NF-kappa B and its binding to the MMP-9 and uPA promoters, and these suppressive effects were further enhanced by PD98059 or SP600125. Moreover, metformin markedly enhanced the anti-metastatic effects of sorafenib. In conclusion, metformin inhibits the migration and invasion of HCC cells by suppressing the ERK/JNK-mediated NF-kappa B-dependent pathway, and thereby reducing uPA and MMP-9 expression. Additionally, combination treatment with metformin and sorafenib yielded synergistic inhibitory effects in suppressing cell migration and invasion of HCC cells. These findings provide insight into the molecular mechanisms involved in the anti-metastatic effects of metformin, as well as its ability to enhance the chemosensitivity of HCC cells to sorafenib.