Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides.
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.
|Year of Publication||
2014 Apr 03
|PubMed Central ID||
R01 CA103866 / CA / NCI NIH HHS / United States
T32 GM007287 / GM / NIGMS NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
K99 CA168940 / CA / NCI NIH HHS / United States
CA103866 / CA / NCI NIH HHS / United States
AI07389 / AI / NIAID NIH HHS / United States
Howard Hughes Medical Institute / United States
CA129105 / CA / NCI NIH HHS / United States
R01 CA129105 / CA / NCI NIH HHS / United States
R00 CA168940 / CA / NCI NIH HHS / United States
T32 AI007389 / AI / NIAID NIH HHS / United States