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Molecular and Cellular Biology / Genetics

Abstract 880: Genetic ablation of the cystine transporter xCT in pancreatic ductal adenocarcinoma inhibits mTORC1, growth, survival and tumor formation: Implications for potentiating chemosensitivity via erastin

Milica Vučetić, Boutaina Daher, Jerome Durivault, Scott K. Parks and Jacques Pouyssegur
Milica Vučetić
1Centre Scientifique de Monaco (CSM), Monaco;
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Boutaina Daher
1Centre Scientifique de Monaco (CSM), Monaco;
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Jerome Durivault
1Centre Scientifique de Monaco (CSM), Monaco;
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Scott K. Parks
1Centre Scientifique de Monaco (CSM), Monaco;
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Jacques Pouyssegur
2Centre Scientifique de Monaco (CSM) & University Côte d'Azur, IRCAN, Centre A. Lacassagne, Nice, France.
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DOI: 10.1158/1538-7445.AM2019-880 Published July 2019
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Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA

Abstract

The lethality of pancreatic ductal adenocarcinomas (PDAC) calls for improved therapeutic strategies. Chemoresistance remains a primary challenge in PDAC treatment, and exploiting oxidative stress might offer novel therapeutic clues. In this regard, we explored the cystine/glutamate exchanger (SLC7A11/xCT) that contributes to the maintenance of the intracellular glutathione (GSH). We deleted xCT via CRISPR-Cas9 in two PDAC cell lines (MiaPaCa-2 and Capan-2) and cultivated xCT-KO clones in the presence of N-acetylcysteine (NAC). In both cell lines, xCT-deletion abolished >90% of 14C-cystine uptake and induced a rapid depletion of GSH following NAC removal. Although several cystine/cysteine transporters have been identified in human cells, our finding demonstrates that, in vitro, xCT is the major actor for GSH synthesis. Consequently, both xCT-KO cell lines exhibited amino-acid stress with ATF4 and GCN2 kinase activation, mTORC1 inhibition, and proliferation arrest followed by ferroptotic cell death. Importantly, tumor growth was also abolished in both KO cell lines indicating the key role of xCT in cellular cysteine availability in vivo. Moreover, the rapid depletion of intracellular GSH in xCT-KO cells led to accumulation of lipid peroxides and cell swelling, both being prevented by vitamin E or iron chelation, two hallmarks of cell death by ferroptosis. Finally, in vitro pharmacological inhibition of xCT by erastin (1μM) phenocopied xCT-KO and potentiated the cytotoxic effects of both gemcitabine and cisplatin in these PDAC cell lines. In conclusion, our findings strongly support the concept that xCT inhibition, by its dual induction of nutritional and oxidative cellular stresses, has the great potential of a successful anticancer strategy.

Note: This abstract was not presented at the meeting.

Citation Format: Milica Vučetić, Boutaina Daher, Jerome Durivault, Scott K. Parks, Jacques Pouyssegur. Genetic ablation of the cystine transporter xCT in pancreatic ductal adenocarcinoma inhibits mTORC1, growth, survival and tumor formation: Implications for potentiating chemosensitivity via erastin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 880.

  • ©2019 American Association for Cancer Research.
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Cancer Research: 79 (13 Supplement)
July 2019
Volume 79, Issue 13 Supplement
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Abstract 880: Genetic ablation of the cystine transporter xCT in pancreatic ductal adenocarcinoma inhibits mTORC1, growth, survival and tumor formation: Implications for potentiating chemosensitivity via erastin
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Abstract 880: Genetic ablation of the cystine transporter xCT in pancreatic ductal adenocarcinoma inhibits mTORC1, growth, survival and tumor formation: Implications for potentiating chemosensitivity via erastin
Milica Vučetić, Boutaina Daher, Jerome Durivault, Scott K. Parks and Jacques Pouyssegur
Cancer Res July 1 2019 (79) (13 Supplement) 880; DOI: 10.1158/1538-7445.AM2019-880

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Abstract 880: Genetic ablation of the cystine transporter xCT in pancreatic ductal adenocarcinoma inhibits mTORC1, growth, survival and tumor formation: Implications for potentiating chemosensitivity via erastin
Milica Vučetić, Boutaina Daher, Jerome Durivault, Scott K. Parks and Jacques Pouyssegur
Cancer Res July 1 2019 (79) (13 Supplement) 880; DOI: 10.1158/1538-7445.AM2019-880
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