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Published April 21, 2017 | Published + Supplemental Material
Journal Article Open

The glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility

Abstract

As noted by Warburg, many cancer cells depend on the consumption of glucose. We performed a genetic screen to identify factors responsible for glucose addiction and recovered the two subunits of the xCT antiporter (system xc−), which plays an antioxidant role by exporting glutamate for cystine. Disruption of the xCT antiporter greatly improves cell viability after glucose withdrawal, because conservation of glutamate enables cells to maintain mitochondrial respiration. In some breast cancer cells, xCT antiporter expression is upregulated through the antioxidant transcription factor Nrf2 and contributes to their requirement for glucose as a carbon source. In cells carrying patient-derived mitochondrial DNA mutations, the xCT antiporter is upregulated and its inhibition improves mitochondrial function and cell viability. Therefore, although upregulation of the xCT antiporter promotes antioxidant defence, it antagonizes glutamine metabolism and restricts nutrient flexibility. In cells with mitochondrial dysfunction, the potential utility of xCT antiporter inhibition should be further tested.

Additional Information

© The Author(s) 2017. Received: 30 August 2016. Accepted: 24 February 2017. Published online: 21 April 2017. Hap1 cells were generously provided by Thijn Brummelkamp (Netherlands Cancer Institute), and SK-BR-3 and MDA-MB-231 cells were provided by Raymond Deshaies (Caltech). We also thank Hsiuchen Chen for insightful discussions and comments. This work was supported by a grant from the National Institute of Health (GM110039) to D.C.C., and grants from the Mary Kay Foundation, the V Foundation for Cancer Research and the Sidney Kimmel Foundation to M.J. Author Contributions: C.-S.S. and D.C.C. conceived the overall project, with contributions from P.M. C.-S.S. performed the majority of the experimental work. P.M. performed some experiments with cybrid cell lines, which were provided by V.C. and M.D'A. J.D.W. and M.J. performed and analysed the mass spectrometry studies. C.-S.S. and D.C.C. wrote the paper, and all authors provided input. The authors declare no competing financial interests.

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August 19, 2023
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