Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides

By Kıvanç Birsoy, Richard L. Possemato, Franziska K. Lorbeer, Erol C Bayraktar, P. Thiru, Burcu Yucel, Tim Wang, Walter W. Chen, C. Clish, David M. Sabatini. Nature, 2014

686 citations recorded by the source corpus.

As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues, cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here we developed a continuous-flow culture apparatus (Nutrostat) for maintaining proliferating cells in low-nutrient media for long periods of time, and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low-glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNA interference (RNAi) screen pinpointed mitochondrial oxidative phosphorylation (OXPHOS) as the major pathway required for optimal proliferation in low glucose. We found that cell lines most sensitive to low glucose are defective in the OXPHOS upregulation that is normally caused by glucose limitation as a result of either mitochondrial DNA (mtDNA) mutations in complex I genes or impaired glucose utilization. These defects predict sensitivity to biguanides, antidiabetic drugs that inhibit OXPHOS, when cancer cells are grown in low glucose or as tumour xenografts. Notably, the biguanide sensitivity of cancer cells with mtDNA mutations was reversed by ectopic expression of yeast NDI1, a ubiquinone oxidoreductase that allows bypass of complex I function. Thus, we conclude that mtDNA mutations and impaired glucose utilization are potential biomarkers for identifying tumours with increased sensitivity to OXPHOS inhibitors.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/10912aa7100eb2ee04a3ea5abc9f4a7134478f9e

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Citations in the corpus

Mitochondria and Cancer (2016, background): “Tumor cells with sensitivity to low glucose and reduced oxidative phosphorylation are sensitized to biguanides that inhibit complex I (Birsoy et al., 2014).”
Metabolic competition in the tumor microenvironment is a driver of cancer progression (2015, background): “Tumor cells cultured for extended periods of time in low glucose adapt by increasing respiration (Birsoy et al., 2014), indicating that modulating nutrients can alter metabolism.”
An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis (2015, background): “These results are consistent with the previous finding that cells having heteroplasmic mitochondrial DNA mutations that partially impair the ETC are hypersensitive to phenformin (Birsoy et al., 2014).”
Mitochondrial reactive oxygen species and cancer (2014, background): “this model, large levels of heteroplasmy sensitized cells to growth inhibition under low glucose [85].”
Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis (2014, neutral): “Our results are consistent with a recent report demonstrating another biguanide phenformin exerts its anti-tumor effects by inhibiting complex I (Birsoy et al., 2014).”
Fundamentals of cancer metabolism (2016, background): “Like metformin, the biguanide phenformin exhibits anticancer properties by inhibiting mitochondrial complex I (165).”
Oxidative Phosphorylation as an Emerging Target in Cancer Therapy (2018, background): “Indeed, recentworkhas shown that phenformin causes growthdelayof xenograft tumors, and that this is also likely mediated by complex I inhibition (15, 33, 35, 49, 51).”
Autophagy, Metabolism, and Cancer (2015, neutral): “Tumors with increased glucose dependence due to mitochondrial mutations are more sensitive to biguanides (83).”
Understanding the intersections between metabolism and cancer biology (2017, neutral): “Second, cancer cells retain the capacity to increase fermentation when respiration is inhibited, and also can increase respiration when mitochondria are uncoupled (Andrzejewski et al., 2014; Birsoy et al., 2014).”