title: K‑ras gene mutation as a predictor of cancer cell responsiveness to metformin.
abstract: An increasing number of studies support the use of metformin, a common antidiabetic drug, as a novel anticancer therapeutic. However, its mechanism of action has yet to be identified. In the current study, metformin was observed to effectively inhibit the growth of the K-ras mutant but not wild-type tumors in vivo. The antitumor effects of metformin were mediated by the induction of apoptosis and inhibition of proliferation in vivo. In addition, metformin induced apoptosis in the K-ras mutant tumors, A549 and PANC-1, but not in the K-ras wild-type tumor, A431, in vitro. Similarly, at lower concentrations, metformin inhibited cell proliferation in the K-ras mutant, but not in the K-ras wild-type tumor cells in vitro. These observations indicate that tumors with K-ras mutations are sensitive to metformin therapy. In addition, metformin significantly arrested K-ras mutant and wild-type tumor cells in G1 phase in vitro and metformin downregulated two important downstream effectors of the Ras signaling pathway in K-ras mutant tumors. Metformin was concluded to function as a potential K-ras-targeting agent that has potential for cancer therapy.
authors.affiliation: Department of Thoracic Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ma
authors.forename: Fu-Chun
authors.initials: FC
authors.lastname: Guo
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Hua-Shan
authors.initials: HS
authors.lastname: Shi
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000627:therapeutic use* / Q000633:toxicity; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008687:Metformin; D018631:ras Proteins