Low glucose-sensitive cancer cells have impaired OXPHOS upregulation and respond to phenformin.
Major finding: Low glucose-sensitive cancer cells have impaired OXPHOS upregulation and respond to phenformin.
Concept: Complex I mtDNA mutations or defective glucose utilization confer sensitivity to glucose limitation.
Impact: Glucose utilization defects or mtDNA mutations may identify tumors more likely to respond to biguanides.
Rapidly proliferating tumors must satisfy energetic demands for cell growth and replication and adapt to diminished nutrient concentrations within the tumor microenvironment. In an effort to identify cancer cell metabolic dependencies under chronic low-glucose conditions, Birsoy and colleagues used a continuous-flow culture system that maintains cells at a steady low-glucose concentration to perform a long-term competitive proliferation assay of 28 pooled patient-derived cancer cell lines in culture. The proliferative response to glucose limitation was diverse, as most cell lines were unaffected, but others showed impaired or enhanced growth. An RNAi screen of human metabolic genes identified the nuclear-encoded components of mitochondrial oxidative phosphorylation (OXPHOS) as necessary for optimal proliferation of cancer cells under low-glucose conditions. Consistent with this finding, low glucose-sensitive cell lines had a significantly reduced ability to increase their oxygen consumption rates under glucose limitation that correlated with either reduced expression of GLUT3 and GLUT1 glucose transporters or heteroplasmic mutations in the mitochondrial genome-encoded (mtDNA) respiratory chain complex I subunits, suggesting that impaired glucose utilization and mitochondrial dysfunction are two distinct mechanisms that confer low-glucose sensitivity. Interestingly, cancer cell lines with these metabolic features were 5- to 20-fold more sensitive to OXPHOS inhibition with phenformin, a potent biguanide compound used as an antidiabetic agent, under glucose limitation in vitro and in a murine tumor xenograft model. Overexpression of GLUT3 in cells with glucose utilization defects or ectopic expression of the yeast ubiquinone oxidoreductase NDI1 to allow bypass of complex I in cells with mtDNA complex I mutations rescued the defects in oxygen consumption rate and proliferation caused by glucose limitation as well as phenformin sensitivity in vitro and in mouse tumor xenografts. Together, these findings suggest that impaired glucose utilization and mtDNA complex I mutations may be used to predict sensitivity of tumors to OXPHOS inhibition with biguanides.
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