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Stem Cell Factor SOX2 Confers Ferroptosis Resistance in Lung Cancer via Upregulation of SLC7A11
Cancer Research ( IF 12.5 ) Pub Date : 2021-10-15 , DOI: 10.1158/0008-5472.can-21-0567
Xinbo Wang 1 , Yueqing Chen 2, 3 , Xudong Wang 1 , Hongling Tian 1 , Yanjin Wang 1 , Jiali Jin 1 , Zezhi Shan 1 , Yu'e Liu 1 , Zhenyu Cai 1 , Xinyuan Tong 2 , Yi Luan 1 , Xiao Tan 1 , Bing Luan 4 , Xin Ge 5 , Hongbin Ji 2, 6, 7 , Xuejun Jiang 8 , Ping Wang 1
Affiliation  

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. Significance: This study uncovers a SOX2–SLC7A11 regulatory axis that confers resistance to ferroptosis in lung cancer stem-like cells.

中文翻译:

干细胞因子 SOX2 通过上调 SLC7A11 赋予肺癌铁死亡抗性

铁死亡是由代谢功能障碍引起的脂质过氧化依赖性细胞死亡。铁死亡相关酶是癌症治疗的有希望的治疗靶点。然而,由于耐药性和其他很大程度上未知的潜在机制,此类治疗策略显示出有限的疗效。在这里,我们报告胱氨酸转运蛋白 SLC7A11 在肺癌干细胞样细胞 (CSLC) 中上调,并且可以被干细胞转录因子 SOX2 激活。SLC7A11 启动子中 SOX2 结合位点的突变降低了 SLC7A11 的表达并增加了癌细胞对铁死亡的敏感性。SOX2 在 Cys265 的氧化抑制了其活性并降低了 CSLC 的自我更新能力。此外,具有高 SOX2 表达的肿瘤对铁死亡的抵抗力更强,在小鼠和人肺癌组织中,SLC7A11 的表达与 SOX2 呈正相关。总之,我们的研究提供了癌细胞逃避铁死亡的机制,并表明 SOX2 的氧化可以成为癌症治疗的潜在治疗靶点。意义:这项研究揭示了一个 SOX2-SLC7A11 调节轴,它赋予肺癌干细胞样细胞对铁死亡的抵抗力。
更新日期:2021-10-15
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