Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis

Takla Griss 1, 2 Emma Vincent 1, 2 Robert Egnatchik 3, 4, 5 Jocelyn Chen 1, 2 Eric Ma 1, 2 Brandon Faubert 1, 2 Benoit Viollet 6 Ralph Deberardinis 3, 4, 5 Russell Jones 1, 2, *
* Corresponding author
1 Goodman Cancer Research Centre [Montréal, QC, Canada]
2 Department of Physiology [Montréal]
3 Children's Medical Center Research Institute [Dallas, TX, États-Unis]
4 McDermott Center for Human Growth and Development [Dallas, TX, États-Unis]
5 Harold C. Simmons Comprehensive Cancer Center [Dallas, TX, États-Unis]
6 IC UM3 (UMR 8104 / U1016) - Institut Cochin
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.
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Takla Griss, Emma Vincent, Robert Egnatchik, Jocelyn Chen, Eric Ma, et al.. Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis. PLoS Biology, Public Library of Science, 2015, 13 (12), pp.e1002309. ⟨10.1371/journal.pbio.1002309⟩. ⟨inserm-02135382⟩

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