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

Chun-Shik Shin, Prashant Mishra, Jeramie D. Watrous, Valerio Carelli, Marilena D’Aurelio, Mohit Jain and David C. Chan ()
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Chun-Shik Shin: California Institute of Technology
Prashant Mishra: California Institute of Technology
Jeramie D. Watrous: University of California
Valerio Carelli: IRCCS Istituto delle Scienze Neurologiche di Bologna
Marilena D’Aurelio: Weill Medical College of Cornell University
Mohit Jain: University of California
David C. Chan: California Institute of Technology

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15074

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