Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway
Disruption of xCT inhibits cancer cell metastasis via the caveolin-1/β-catenin pathway
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DOI：
10.1038/onc.2008.414
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发表时间：
2009-01-29
期刊：
影响因子：
8
通讯作者：
Li, W.
中科院分区：
文献类型：
--
作者：
Chen, R-S;Song, Y-M;Li, W.
xCT是胱氨酸/谷氨酸转运体xc-系统的功能亚基，在维持细胞内谷胱甘肽和氧化还原平衡中起关键作用。破坏xCT可显著抑制多种癌症的生长，包括淋巴瘤、神经胶质瘤、前列腺癌和乳腺癌。然而，xCT在肿瘤转移中的作用在很大程度上仍然未知。在这项研究中，xCT（+/+）和xCT（-/-）黑素细胞都用于评估xCT在粘附中的作用。在食管癌细胞系KYSE 150中，xCT活性被抑制剂柳氮磺胺吡啶（SASP）或xCT siRNA抑制。我们发现，破坏xCT增强同型细胞-细胞粘附和减弱细胞-细胞外基质粘附。SASP对KYSE 150细胞的体外侵袭和裸鼠实验性转移均有明显的抑制作用。当xCT缺乏时，小窝蛋白-1上调，β-连环蛋白被募集到质膜，随后抑制β-连环蛋白的转录活性。进一步的研究表明，活性氧诱导p38 MAPK活化，从而上调caveolin-1表达，抑制肿瘤细胞的侵袭。这些结果首次确立了xCT在肿瘤转移中的作用，并暗示了癌症治疗的潜在靶点。
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.