mTOR-dependent upregulation of xCT blocks melanin synthesis and promotes tumorigenesis
mTOR-dependent upregulation of xCT blocks melanin synthesis and promotes tumorigenesis
复制标题
mTOR 依赖性 xCT 上调可阻断黑色素合成并促进肿瘤发生
DOI：
10.1038/s41418-019-0274-0
复制
发表时间：
2019-10-01
影响因子：
12.4
通讯作者：
Zhang, Hongbing
中科院分区：
文献类型：
--
作者：
Li, Chunjia;Chen, Hongyu;Zhang, Hongbing
TSC 1或TSC 2的缺失通过mTOR信号通路的激活引起结节性硬化症（TSC）。TSC的两个突出特征是皮肤病变，包括黑色素减少斑和多器官良性肿瘤，其分子改变在很大程度上是未知的。我们在此报告，XC-胱氨酸/谷氨酸反向转运蛋白（xCT）在Tsc 2-/-或Pten-/-细胞、Tsc 1敲除小鼠组织和Tsc 2缺陷的人肾肿瘤中升高。xCT通过mTOR介导的Oct 1信号级联在转录上增强。增强xCT通过mTOR信号通路导致Tsc 1皮肤基因敲除小鼠真黑素减少和褐黑素升高。xCT的破坏抑制Pten-null细胞和Tsc 2-null细胞的增殖和成瘤。mTOR过度活跃的细胞对mTOR或xCT的抑制剂更敏感。mTOR和xCT的组合抑制协同阻断了mTOR高活性细胞的增殖和肿瘤发生。因此，xCT的致癌mTOR激活是异常黑色素合成和肿瘤发生之间的关键联系。我们认为xCT是TSC和其他异常mTOR相关疾病的新治疗靶点。
Loss of either TSC1 or TSC2 causes tuberous sclerosis complex (TSC) via activation of mTOR signaling pathway. The two prominent features of TSC are skin lesions including hypomelanic macules and benign tumors in multiple organs, whose molecular alterations are largely unknown. We report here that Xc−cystine/glutamate antiporter (xCT) was elevated inTsc2−/−orPten−/−cells,Tsc1knockout mouse tissues andTSC2-deficient human kidney tumor. xCT was transcriptionally boosted by mTOR-mediated Oct1 signaling cascade. Augmented xCT led to reduction of eumelanin and elevation of pheomelanin inTsc1skin knockout mice through mTOR signaling pathway. Disruption of xCT suppressed the proliferation and tumorigenesis ofPten-null cells andTsc2-null cells. mTOR hyperactive cells were more sensitive to inhibitors of mTOR or xCT. Combined inhibition of mTOR and xCT synergistically blocked the propagation and oncogenesis of mTOR hyperactive cells. Therefore, oncogenic mTOR activation of xCT is a key connection between aberrant melanin synthesis and tumorigenesis. We suggest that xCT is a novel therapeutic target for TSC and other aberrant mTOR-related diseases.