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, David C. Chan

Research output: Contribution to journalArticle

55 Scopus citations

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 xCTantiporter 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 xCTantiporter inhibition should be further tested.

Original languageEnglish (US)
Article number15074
JournalNature communications
Volume8
DOIs
StatePublished - 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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