Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy.
Cells. 2021 Jan 8;10(1):108. doi: 10.3390/cells10010108.
The cystine/glutamate antiporter xCT is a tumor-associated antigen that has been newly identified in many cancer types. By participating in glutathione biosynthesis, xCT protects cancer cells from oxidative stress conditions and ferroptosis, and contributes to metabolic reprogramming, thus promoting tumor progression and chemoresistance. Moreover, xCT is overexpressed in cancer stem cells. These features render xCT a promising target for cancer therapy, as has been widely reported in the literature and in our work on its immunotargeting. Interestingly, studies on the TP53 gene have revealed that both wild-type and mutant p53 induce the post-transcriptional down modulation of xCT, contributing to ferroptosis. Moreover, APR-246, a small molecule drug that can restore wild-type p53 function in cancer cells, has been described as an indirect modulator of xCT expression in tumors with mutant p53 accumulation, and is thus a promising drug to use in combination with xCT inhibition. This review summarizes the current knowledge of xCT and its regulation by p53, with a focus on the crosstalk of these two molecules in ferroptosis, and also considers some possible combinatorial strategies that can make use of APR-246 treatment in combination with anti-xCT immunotargeting.
胱氨酸/谷氨酸反向转运蛋白 xCT 是一种新发现的肿瘤相关抗原，存在于许多癌症类型中。通过参与谷胱甘肽的生物合成，xCT 保护癌细胞免受氧化应激和铁死亡的影响，并促进代谢重编程，从而促进肿瘤的进展和化疗耐药性。此外，xCT 在肿瘤干细胞中过度表达。这些特性使 xCT 成为癌症治疗的一个有前途的靶点，这在文献中以及我们对其免疫靶向的研究中都有广泛报道。有趣的是，对 TP53 基因的研究表明，野生型和突变型 p53 都能诱导 xCT 的转录后下调，从而促进铁死亡。此外，APR-246 是一种小分子药物，可以恢复癌细胞中野生型 p53 的功能，已被描述为突变型 p53 积累肿瘤中 xCT 表达的间接调节剂，因此是一种有前途的药物，可以与 xCT 抑制联合使用。这篇综述总结了目前关于 xCT 及其受 p53 调节的知识，重点讨论了这两种分子在铁死亡中的相互作用，并考虑了一些可能的联合策略，可以利用 APR-246 治疗与抗 xCT 免疫靶向相结合。
