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

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 beta-catenin was recruited to the plasma membrane when xCT was deficient, which were followed by the inhibition of beta-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.