title: 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.
abstract: 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-κB 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-κB-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.
authors.affiliation: Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Hsieh
authors.forename: Jen-Pi
authors.initials: JP
authors.lastname: Tsai
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
authors.forename: Meng-Ju
authors.initials: MJ
authors.lastname: Tang
authors.forename: Yi-Hsien
authors.initials: YH
authors.lastname: Hsieh
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics* / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D010671:Phenylurea Compounds; D009536:Niacinamide; D008687:Metformin; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4; D014568:Urokinase-Type Plasminogen Activator; D020780:Matrix Metalloproteinase 9