Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis

Takla Griss, Emma E Vincent, Robert Egnatchik, Jocelyn Chen, Eric H Ma, Brandon Faubert, Benoit Viollet, Ralph J DeBerardinis, Russell G Jones

Research output: Contribution to journalArticle (Academic Journal)peer-review

164 Citations (Scopus)


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.

Original languageEnglish
Article numbere1002309
JournalPLoS Biology
Issue number12
Publication statusPublished - 1 Dec 2015


  • AMP-Activated Protein Kinases
  • Animals
  • Antineoplastic Agents
  • Carrier Proteins
  • Cell Line, Tumor
  • Cell Proliferation
  • Cells, Cultured
  • Citric Acid Cycle
  • Drug Resistance, Neoplasm
  • Electron Transport Chain Complex Proteins
  • Embryo, Mammalian
  • Eukaryotic Initiation Factors
  • Humans
  • Hypoglycemic Agents
  • Lipid Metabolism
  • Metformin
  • Mice
  • Mice, Knockout
  • Mitochondria
  • Mutation
  • Neoplasms
  • Phosphoproteins
  • Protein-Serine-Threonine Kinases
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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