Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance
Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance
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DOI：
10.1073/pnas.1821323116
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发表时间：
2019-05-07
影响因子：
11.1
通讯作者：
Sorensen, Poul H.
中科院分区：
文献类型：
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作者：
Lim, Jonathan K. M.;Delaidelli, Alberto;Sorensen, Poul H.
RAS 原癌基因家族是人类癌症中最常见的突变基因之一，可预测不良的临床结果。致癌 RAS 转化的几种机制已得到充分记录，包括通过 RAF-MEK-ERK 增殖途径以及 PI3K-AKT 促生存途径的组成型信号传导。值得注意的是，氧化还原平衡的控制也被提议有助于 RAS 转化。然而，活性氧（ROS）和抗氧化剂之间的稳态在细胞中具有相反的作用，最终如何影响RAS介导的转化和肿瘤进展仍然是一个有争议的问题，并且所涉及的机制尚未完全阐明。在这里，我们发现致癌 KRAS 通过提高细胞内 GSH 水平来保护成纤维细胞免受氧化应激。使用全转录组方法，我们发现这归因于 xCT（编码胱氨酸/谷氨酸逆向转运蛋白的基因）的转录上调。这与 xCT 的功能一致，xCT 介导胱氨酸的摄取，胱氨酸是 GSH 生物合成的前体。此外，我们的结果表明，RAS-RAF-MEK-ERK 信号级联下游的 ETS-1 转录因子直接反式激活 xCT 启动子，与 ATF4 内质网应激相关转录因子协同作用。引人注目的是，xCT 通过减轻氧化应激而被发现对于体外和体内 KRAS 介导的致癌转化至关重要，因为 xCT 的敲低会严重损害由 KRAS 转化细胞建立的肿瘤异种移植物的生长。总体而言，这项研究揭示了致癌 RAS 维持细胞内氧化还原平衡的机制，并确定了 xCT 在支持 RAS 诱导的转化和致瘤性方面的意想不到的作用。
The RAS family of proto-oncogenes are among the most commonly mutated genes in human cancers and predict poor clinical outcome. Several mechanisms underlying oncogenic RAS transformation are well documented, including constitutive signaling through the RAF-MEK-ERK proproliferative pathway as well as the PI3K-AKT prosurvival pathway. Notably, control of redox balance has also been proposed to contribute to RAS transformation. However, how homeostasis between reactive oxygen species (ROS) and antioxidants, which have opposing effects in the cell, ultimately influence RAS-mediated transformation and tumor progression is still a matter of debate and the mechanisms involved have not been fully elucidated. Here, we show that oncogenic KRAS protects fibroblasts from oxidative stress by enhancing intracellular GSH levels. Using a whole transcriptome approach, we discovered that this is attributable to transcriptional up-regulation of xCT, the gene encoding the cystine/glutamate antiporter. This is in line with the function of xCT, which mediates the uptake of cystine, a precursor for GSH biosynthesis. Moreover, our results reveal that the ETS-1 transcription factor downstream of the RAS-RAF-MEK-ERK signaling cascade directly transactivates the xCT promoter in synergy with the ATF4 endoplasmic reticulum stress-associated transcription factor. Strikingly, xCT was found to be essential for oncogenic KRAS-mediated transformation in vitro and in vivo by mitigating oxidative stress, as knock-down of xCT strongly impaired growth of tumor xenografts established from KRAS-transformed cells. Overall, this study uncovers a mechanism by which oncogenic RAS preserves intracellular redox balance and identifies an unexpected role for xCT in supporting RAS-induced transformation and tumorigenicity.