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xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction

  • Author(s): Timmerman, Luika A
  • Cobler, Lara
  • Zhang, Hui
  • Suri, Poojan
  • Park, Catherine C
  • et al.
Abstract

About 3 million US cancer patients and 1.7 million EU cancer patients receivedmultiple doses of radiation therapy (RT) in 2012, with treatment duration limited bynormal adjacent tissue damage. Tumor-specific sensitization could allow treatmentwith lower radiation doses, reducing normal tissue damage. This is a longstanding,largely unrealized therapeutic goal. The cystine:glutamate exchanger xCT is expressedon poor prognosis subsets of most solid tumors, but not on most normal cells. xCTprovides cells with environmental cystine for enhanced glutathione synthesis.Glutathione is used to control reactive oxygen species (ROS), which are therapeuticeffectors of RT. We tested whether xCT inhibition would sensitize xCT+ tumor cells toionizing radiation. We found that pretreatment with the xCT inhibitor erastin potentlysensitized xCT+ but not xCT- cells, in vitro and in xenograft. Similarly, targeted geneinactivation also sensitized cells, and both modes of sensitization were overcome byglutathione supplementation. Sensitization prolongs DNA damage signaling, increasesgenome instability, and enhances cell death, revealing an unforeseen role for cysteinein genome integrity maintenance. We conclude that an xCT-specific therapeutic wouldprovide tumor-specific sensitization to RT, allowing treatment with lower radiationdoses, and producing far fewer side effects than other proposed sensitizers. Our dataspeaks to the need for the rapid development of such a drug.

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