Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

William W. Wheaton, Samuel E. Weinberg, Robert B. Hamanaka, Saul Soberanes, Lucas B. Sullivan, Elena Anso, Andrea Glasauer, Eric Dufour, Gokhan M. Mutlu, G. R. Scott Budigner, Navdeep S. Chandel

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426 Scopus citations

Abstract

Recent epidemiological and laboratory-based studies suggest that the anti-diabetic drug metformin prevents cancer progression. How metformin diminishes tumor growth is not fully understood. In this study, we report that in human cancer cells, metformin inhibits mitochondrial complex I (NADH dehydrogenase) activity and cellular respiration. Metformin inhibited cellular proliferation in the presence of glucose, but induced cell death upon glucose deprivation, indicating that cancer cells rely exclusively on glycolysis for survival in the presence of metformin. Metformin also reduced hypoxic activation of hypoxia-inducible factor 1 (HIF-1). All of these effects of metformin were reversed when the metformin-resistant Saccharomyces cerevisiae NADH dehydrogenase NDI1 was overexpressed. In vivo, the administration of metformin to mice inhibited the growth of control human cancer cells but not those expressing NDI1. Thus, we have demonstrated that metformin's inhibitory effects on cancer progression are cancer cell autonomous and depend on its ability to inhibit mitochondrial complex I.

Original languageEnglish (US)
Article numbere02242
JournaleLife
Volume2014
Issue number3
DOIs
StatePublished - May 13 2014

ASJC Scopus subject areas

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

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    Wheaton, W. W., Weinberg, S. E., Hamanaka, R. B., Soberanes, S., Sullivan, L. B., Anso, E., Glasauer, A., Dufour, E., Mutlu, G. M., Scott Budigner, G. R., & Chandel, N. S. (2014). Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. eLife, 2014(3), [e02242]. https://doi.org/10.7554/eLife.02242