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

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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.

Original languageEnglish (US)
Article numbere1002309
JournalPLoS Biology
Volume13
Issue number12
DOIs
StatePublished - Dec 1 2015

Fingerprint

metformin
Metformin
Biosynthesis
Cell proliferation
cell proliferation
Cell Proliferation
biosynthesis
Neoplasms
biguanides
Biguanides
Cell growth
Glutamine
glutamine
Tumors
cell growth
Cells
Carboxylation
NADH dehydrogenase (ubiquinone)
Electron Transport Complex I
Lipids

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Cite this

Griss, T., Vincent, E. E., Egnatchik, R., Chen, J., Ma, E. H., Faubert, B., ... Jones, R. G. (2015). Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis. PLoS Biology, 13(12), [e1002309]. https://doi.org/10.1371/journal.pbio.1002309

Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis. / Griss, Takla; Vincent, Emma E.; Egnatchik, Robert; Chen, Jocelyn; Ma, Eric H.; Faubert, Brandon; Viollet, Benoit; DeBerardinis, Ralph J.; Jones, Russell G.

In: PLoS Biology, Vol. 13, No. 12, e1002309, 01.12.2015.

Research output: Contribution to journalArticle

Griss, T, Vincent, EE, Egnatchik, R, Chen, J, Ma, EH, Faubert, B, Viollet, B, DeBerardinis, RJ & Jones, RG 2015, 'Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis', PLoS Biology, vol. 13, no. 12, e1002309. https://doi.org/10.1371/journal.pbio.1002309
Griss, Takla ; Vincent, Emma E. ; Egnatchik, Robert ; Chen, Jocelyn ; Ma, Eric H. ; Faubert, Brandon ; Viollet, Benoit ; DeBerardinis, Ralph J. ; Jones, Russell G. / Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis. In: PLoS Biology. 2015 ; Vol. 13, No. 12.
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