Stem Cell Factor SOX2 Confers Ferroptosis Resistance in Lung Cancer via Upregulation of SLC7A11.
Stem Cell Factor SOX2 Confers Ferroptosis Resistance in Lung Cancer via Upregulation of SLC7A11.
复制标题
干细胞因子 SOX2 通过上调 SLC7A11 赋予肺癌铁死亡抗性
DOI：
10.1158/0008-5472.can-21-0567
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发表时间：
2021-10-15
期刊：
影响因子：
11.2
通讯作者：
Wang P
中科院分区：
文献类型：
--
作者：
Wang X;Chen Y;Wang X;Tian H;Wang Y;Jin J;Shan Z;Liu Y;Cai Z;Tong X;Luan Y;Tan X;Luan B;Ge X;Ji H;Jiang X;Wang P
铁凋亡是一种由代谢功能障碍引起的脂质过氧化依赖性细胞死亡。铁蛋白分解相关酶是癌症治疗的有希望的治疗靶点。然而，这种治疗策略由于耐药性和其他基本未知的潜在机制而显示出有限的功效。在这里，我们报告胱氨酸转运蛋白SLC 7A 11在肺癌干细胞样细胞（CSLC）中上调，并可被干细胞转录因子SOX 2激活。SLC 7A 11启动子中SOX 2结合位点的突变降低了SLC 7A 11的表达，并增加了癌细胞对铁凋亡的敏感性。SOX 2在Cys 265位的氧化抑制了其活性，降低了CSLCs的自我更新能力。此外，具有高SOX 2表达的肿瘤对铁凋亡更有抵抗力，并且在小鼠和人肺癌组织中，SLC 7A 11表达与SOX 2正相关。总之，我们的研究提供了一种癌细胞逃避铁凋亡的机制，并表明SOX 2的氧化可以成为癌症治疗的潜在治疗靶点。这项研究揭示了SOX 2-SLC 7A 11调节轴，该轴赋予肺癌干细胞样细胞对铁凋亡的抗性。
Ferroptosis is a lipid peroxidation-dependent cell death caused by metabolic dysfunction. Ferroptosis-associated enzymes are promising therapeutic targets for cancer treatment. However, such therapeutic strategies show limited efficacy due to drug resistance and other largely unknown underlying mechanisms. Here we report that cystine transporter SLC7A11 is upregulated in lung cancer stem-like cells (CSLC) and can be activated by stem cell transcriptional factor SOX2. Mutation of SOX2 binding site in SLC7A11 promoter reduced SLC7A11 expression and increased sensitivity to ferroptosis in cancer cells. Oxidation at Cys265 of SOX2 inhibited its activity and decreased the self-renewal capacity of CSLCs. Moreover, tumors with high SOX2 expression were more resistant to ferroptosis, and SLC7A11 expression was positively correlated with SOX2 in both mouse and human lung cancer tissue. Together, our study provides a mechanism by which cancer cells evade ferroptosis and suggests that oxidation of SOX2 can be a potential therapeutic target for cancer treatment. This study uncovers a SOX2-SLC7A11 regulatory axis that confers resistance to ferroptosis in lung cancer stem-like cells.