Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis

PLoS Biol. 2015 Dec 1;13(12):e1002309. doi: 10.1371/journal.pbio.1002309. eCollection 2015 Dec.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics
  • AMP-Activated Protein Kinases / metabolism
  • Adaptor Proteins, Signal Transducing
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cells, Cultured
  • Citric Acid Cycle / drug effects*
  • Drug Resistance, Neoplasm
  • Electron Transport Chain Complex Proteins / genetics
  • Electron Transport Chain Complex Proteins / metabolism
  • Embryo, Mammalian / cytology
  • Eukaryotic Initiation Factors / genetics
  • Eukaryotic Initiation Factors / metabolism
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Lipid Metabolism / drug effects
  • Metformin / pharmacology*
  • Mice
  • Mice, Knockout
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Mutation
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents
  • Carrier Proteins
  • Cell Cycle Proteins
  • Eif4ebp1 protein, mouse
  • Eif4ebp2 protein, mouse
  • Electron Transport Chain Complex Proteins
  • Eukaryotic Initiation Factors
  • Hypoglycemic Agents
  • Phosphoproteins
  • Metformin
  • Stk11 protein, mouse
  • AMPK alpha1 subunit, mouse
  • AMPK alpha2 subunit, mouse
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases