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Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway

Abstract

xCT, the functional subunit of the cystine/glutamate transporter xc- system, plays a critical role in the maintenance of intracellular glutathione and redox balance. Disruption of xCT significantly inhibits the growth of a variety of carcinomas, including lymphoma, glioma, prostate and breast cancer. However, the role of xCT in tumor metastasis remains largely unknown. In this study, both xCT+/+ and xCT−/− melanocytes were used to evaluate the role of xCT in adhesion. xCT activity was suppressed by an inhibitor, sulfasalazine (SASP), or by xCT siRNA in an esophageal cancer cell line, KYSE150. We found that disruption of xCT enhanced homotypic cell–cell adhesion and attenuated cell–extracellular matrix adhesion. SASP significantly inhibited both cell invasion of KYSE150 in vitro and its experimental metastasis in nude mice. Caveolin-1 was upregulated and β-catenin was recruited to the plasma membrane when xCT was deficient, which were followed by the inhibition of β-catenin transcriptional activity. Further study revealed that the upregulation of caveolin-1 and inhibition of tumor cell invasion were mediated by reactive oxygen species-induced p38 MAPK activation. These results first establish the role of xCT in tumor metastasis and implicate a potential target for cancer therapy.

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Acknowledgements

We thank Dr Richard T Swank and Dr Edward K Novak for their invaluable comments on this paper. This study was supported in part by National Basic Research Program of China (2006CB504100, 2006CB500700 and 2007CB947200), grants from National Natural Science Foundation of China (30525007 and 30730049) (to WL or XH).

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Correspondence to Q-M Zhan or W Li.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Chen, RS., Song, YM., Zhou, ZY. et al. Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway. Oncogene 28, 599–609 (2009). https://doi.org/10.1038/onc.2008.414

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