title: Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth.
abstract: The effect of the antidiabetic drug metformin on tumor growth was investigated using the paired isogenic colon cancer cell lines HCT116 p53(+/+) and HCT116 p53(-/-). Treatment with metformin selectively suppressed the tumor growth of HCT116 p53(-/-) xenografts. Following treatment with metformin, we detected increased apoptosis in p53(-/-) tumor sections and an enhanced susceptibility of p53(-/-) cells to undergo apoptosis in vitro when subject to nutrient deprivation. Metformin is proposed to function in diabetes treatment as an indirect activator of AMP-activated protein kinase (AMPK). Treatment with AICAR, another AMPK activator, also showed a selective ability to inhibit p53(-/-) tumor growth in vivo. In the presence of either of the two drugs, HCT116 p53(+/+) cells, but not HCT116 p53(-/-) cells, activated autophagy. A similar p53-dependent induction of autophagy was observed when nontransformed mouse embryo fibroblasts were treated. Treatment with either metformin or AICAR also led to enhanced fatty acid beta-oxidation in p53(+/+) MEFs, but not in p53(-/-) MEFs. However, the magnitude of induction was significantly lower in metformin-treated cells, as metformin treatment also suppressed mitochondrial electron transport. Metformin-treated cells compensated for this suppression of oxidative phosphorylation by increasing their rate of glycolysis in a p53-dependent manner. Together, these data suggest that metformin treatment forces a metabolic conversion that p53(-/-) cells are unable to execute. Thus, metformin is selectively toxic to p53-deficient cells and provides a potential mechanism for the reduced incidence of tumors observed in patients being treated with metformin.
authors.affiliation: Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Buzzai
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.forename: Julian J
authors.initials: JJ
authors.lastname: Lum
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.forename: Fangping
authors.initials: F
authors.lastname: Zhao
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Craig B
authors.initials: CB
authors.lastname: Thompson
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*
chemical_list: D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D008687:Metformin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases