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NADPH debt drives redox bankruptcy: SLC7A11/xCT-mediated cystine uptake as a double-edged sword in cellular redox regulation
Genes & Diseases ( IF 6.9 ) Pub Date : 2020-11-25 , DOI: 10.1016/j.gendis.2020.11.010
Xiaoguang Liu 1 , Yilei Zhang 1 , Li Zhuang 1 , Kellen Olszewski 2 , Boyi Gan 1, 3
Affiliation  

Cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11; also known as xCT) plays a key role in antioxidant defense by mediating cystine uptake, promoting glutathione synthesis, and maintaining cell survival under oxidative stress conditions. Recent studies showed that, to prevent toxic buildup of highly insoluble cystine inside cells, cancer cells with high expression of SLC7A11 (SLC7A11high) are forced to quickly reduce cystine to more soluble cysteine, which requires substantial NADPH supply from the glucose-pentose phosphate pathway (PPP) route, thereby inducing glucose- and PPP-dependency in SLC7A11high cancer cells. Limiting glucose supply to SLC7A11high cancer cells results in significant NADPH “debt”, redox “bankruptcy”, and subsequent cell death. This review summarizes our current understanding of NADPH-generating and -consuming pathways, discusses the opposing role of SLC7A11 in protecting cells from oxidative stress–induced cell death such as ferroptosis but promoting glucose starvation–induced cell death, and proposes the concept that SLC7A11-mediated cystine uptake acts as a double-edged sword in cellular redox regulation. A detailed understanding of SLC7A11 in redox biology may identify metabolic vulnerabilities in SLC7A11high cancer for therapeutic targeting.



中文翻译:

NADPH 债务推动氧化还原破产:SLC7A11/xCT 介导的胱氨酸摄取是细胞氧化还原调节中的双刃剑

胱氨酸/谷氨酸逆向转运蛋白溶质载体家族 7 成员 11(SLC7A11;也称为 xCT)通过介导胱氨酸摄取、促进谷胱甘肽合成和在氧化应激条件下维持细胞存活,在抗氧化防御中发挥关键作用。最近的研究表明,为了防止细胞内高度不溶性胱氨酸的毒性积聚,高表达 SLC7A11(SLC7A11)的癌细胞被迫将胱氨酸快速还原为更易溶的半胱氨酸,这需要葡萄糖-戊糖磷酸途径提供大量 NADPH (PPP) 途径,从而在 SLC7A11癌细胞中诱导葡萄糖和 PPP 依赖性。将葡萄糖供应限制为 SLC7A11癌细胞导致显着的 NADPH“债务”、氧化还原“破产”和随后的细胞死亡。这篇综述总结了我们目前对 NADPH 生成和消耗途径的理解,讨论了 SLC7A11 在保护细胞免受氧化应激诱导的细胞死亡(如铁死亡)但促进葡萄糖饥饿诱导的细胞死亡方面的相反作用,并提出了 SLC7A11-介导的胱氨酸摄取在细胞氧化还原调节中充当双刃剑。对氧化还原生物学中 SLC7A11 的详细了解可以确定 SLC7A11高位 癌症中的代谢弱点,进行治疗靶向。

更新日期:2020-11-25
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