title: Basal Autophagy and Feedback Activation of Akt Are Associated with Resistance to Metformin-Induced Inhibition of Hepatic Tumor Cell Growth.
abstract: While accumulating evidence has shown that the use of the diabetic drug metformin may be beneficial against various tumors in some epidemiological studies, a few studies failed to show the same beneficial effects. The molecular and cellular mechanisms for these conflicting observations are not clear. In this study, we compared the inhibitory effects of cell growth by metformin on several hepatic tumor cell lines: SMMC-7721, HCC-97L, HCC-LM3 and HepG2. While metformin inhibited cell growth in all these cells, we found that SMMC-7721, HCC-97L and HCC-LM3 cells were more resistant than HepG2 cells. Mechanistically, we found that metformin inhibited mTOR in all these hepatic tumor cells. However, SMMC-7721 cells had higher levels of basal autophagy and mTORC2-mediated feedback activation of Akt than HepG2 cells, which may render SMMC-7721 cells to be more resistant to metformin-induced inhibition of cell growth. Similarly, HCC-97L and HCC-LM3 cells also had higher feedback activation of AKT than HepG2 cells, which may also account for their resistance to metformin-induced inhibition of cell growth. Therefore, the various basal autophagy and mTOR activity in different cancer cells may contribute to the controversial findings on the use of metformin in inhibition of cancers in humans.
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, 66160, United States of America.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Yuan-Fei
authors.initials: YF
authors.lastname: Peng
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, 66160, United States of America.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Ni
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, 66160, United States of America.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas, 66160, United States of America.
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Ding
authors.affiliation: Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Fan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008687:Metformin / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D008687:Metformin; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases