Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis

By W. Wheaton, S. Weinberg, R. Hamanaka, S. Soberanes, Lucas B. Sullivan, Elena Ansó, Andrea Glasauer, E. Dufour, G. Mutlu, GR Scott Budigner and 1 more. eLife, 2014

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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. DOI: http://dx.doi.org/10.7554/eLife.02242.001

Subfields: Cancer Research, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/cc51beff017bb4f755941b93486fa1291153a8a0

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Citations in the corpus

Diabetic vascular diseases: molecular mechanisms and therapeutic strategies (2023, background): “Therapeutically, metformin inhibits mitochondrial respiratory chain complex-1 and regulates cellular energy metabolism.(435) In addition, metformin and GLP-1 agonizts regulate the glucagon-lowering hormone glucagon-like peptide-1 and the bile acid pathway and alter the composition of the gut microbi”
Supporting aspartate biosynthesis is an essential function of respiration in proliferating cells (2015, background): “Consistent with this idea, pharmacologic inhibition of ETC activity inhibits tumor growth in several cancer models (Shackelford et al., 2013; Wheaton et al., 2014; Zhang et al., 2014).”
Targeting Metabolism for Cancer Therapy (2017, background): “Although the precise mechanism of metformin action remains controversial (Luengo et al., 2014), recent work has shown that the anti-tumorigenic effect of metformin can at least be partially accounted for by direct mitochondrial complex I inhibition in tumors (Gui et al., 2016; Wheaton et al., 2014).”
Mitochondria in the regulation of innate and adaptive immunity (2015, positive): “It is not clear what the target of metformin in immune cells is but the anti-tumor effects of metformin are through inhibiting mitochondrial complex I (Wheaton et al., 2014).”
Fundamentals of cancer metabolism (2016, background): “Recent studies indicate that metformin acts as an anticancer agent by inhibiting mitochondrial ETC complex I (161).”
An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis (2015, background): “Pharmacological or genetic inhibition of the ETC greatly suppresses cell proliferation (Santidrian et al., 2013; Wheaton et al., 2014) (Figure 1A), but exactly why is unclear.”
Mitochondrial reactive oxygen species and cancer (2014, methodology): “We recently used a metformin insensitive complex I analog to confirm that the anticancer effect of metformin is primarily mediated by specific inhibition of complex I of cancer cells in vivo [104].”
Oxidative Phosphorylation as an Emerging Target in Cancer Therapy (2018, background): “inhibitory effect at least in this model (49).”
Normalization of CD4+ T Cell Metabolism Reverses Lupus (2015, background): “Consistent with its inhibition of mitochondrial complex I (33), Met dose-dependently decreased OCR (Fig.”