title: Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis.
abstract: Metformin is a biguanide widely prescribed to treat Type II diabetes that has gained interest as an antineoplastic agent. Recent work suggests that metformin directly antagonizes cancer cell growth through its actions on complex I of the mitochondrial electron transport chain (ETC). However, the mechanisms by which metformin arrests cancer cell proliferation remain poorly defined. Here we demonstrate that the metabolic checkpoint kinases AMP-activated protein kinase (AMPK) and LKB1 are not required for the antiproliferative effects of metformin. Rather, metformin inhibits cancer cell proliferation by suppressing mitochondrial-dependent biosynthetic activity. We show that in vitro metformin decreases the flow of glucose- and glutamine-derived metabolic intermediates into the Tricarboxylic Acid (TCA) cycle, leading to reduced citrate production and de novo lipid biosynthesis. Tumor cells lacking functional mitochondria maintain lipid biosynthesis in the presence of metformin via glutamine-dependent reductive carboxylation, and display reduced sensitivity to metformin-induced proliferative arrest. Our data indicate that metformin inhibits cancer cell proliferation by suppressing the production of mitochondrial-dependent metabolic intermediates required for cell growth, and that metabolic adaptations that bypass mitochondrial-dependent biosynthesis may provide a mechanism of tumor cell resistance to biguanide activity.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.|Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Takla
authors.initials: T
authors.lastname: Griss
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.|Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Vincent
authors.affiliation: Children's Medical Center Research Institute, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.|McDermott Center for Human Growth and Development, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.|Harold C. Simmons Comprehensive Cancer Center, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Egnatchik
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.|Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Chen
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.|Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Ma
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.|Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Brandon
authors.initials: B
authors.lastname: Faubert
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France.|CNRS, UMR 8104, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Children's Medical Center Research Institute, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.|McDermott Center for Human Growth and Development, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.|Harold C. Simmons Comprehensive Cancer Center, University of Texas, Southwestern Medical Center at Dallas, Dallas, Texas, United States of America.
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: DeBerardinis
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.|Department of Physiology, McGill University, Montreal, Quebec, Canada.
authors.forename: Russell G
authors.initials: RG
authors.lastname: Jones
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002952:Citric Acid Cycle / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C499527:Eif4ebp1 protein, mouse; C491255:Eif4ebp2 protein, mouse; D045222:Electron Transport Chain Complex Proteins; D039642:Eukaryotic Initiation Factors; D007004:Hypoglycemic Agents; D010750:Phosphoproteins; D008687:Metformin; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases