Chen Mei-Chun, Hsu Li-Lin, Wang Sheng-Fan, Pan Yi-Ling, Lo Jeng-Fan, Yeh Tien-Shun, Tseng Ling-Ming, Lee Hsin-Chen
Department and Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.
Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan.
Biomedicines. 2021 Aug 28;9(9):1101. doi: 10.3390/biomedicines9091101.
Cancer cells have the metabolic flexibility to adapt to heterogeneous tumor microenvironments. The integrated stress response (ISR) regulates the cellular adaptation response during nutrient stress. However, the issue of how the ISR regulates metabolic flexibility is still poorly understood. In this study, we activated the ISR using salubrinal in cancer cells and found that salubrinal repressed cell growth, colony formation, and migration but did not induce cell death in a glucose-containing condition. Under a glucose-deprivation condition, salubrinal induced cell death and increased the levels of mitochondrial reactive oxygen species (ROS). We found that these effects of salubrinal and glucose deprivation were associated with the upregulation of xCT (SLC7A11), which functions as an antiporter of cystine and glutamate and maintains the level of glutathione to maintain redox homeostasis. The upregulation of xCT did not protect cells from oxidative stress-mediated cell death but promoted it during glucose deprivation. In addition, the supplementation of ROS scavenger N-acetylcysteine and the maintenance of intracellular levels of amino acids via sulfasalazine (xCT inhibitor) or dimethyl-α-ketoglutarate decreased the levels of mitochondrial ROS and protected cells from death. Our results suggested that salubrinal enhances cancer cell death during glucose deprivation through the upregulation of xCT and mitochondrial oxidative stress.
癌细胞具有代谢灵活性，能够适应异质性肿瘤微环境。整合应激反应（ISR）在营养应激期间调节细胞适应性反应。然而，ISR如何调节代谢灵活性这一问题仍知之甚少。在本研究中，我们在癌细胞中使用水杨醛激活ISR，发现在含葡萄糖的条件下，水杨醛抑制细胞生长、集落形成和迁移，但不诱导细胞死亡。在葡萄糖剥夺条件下，水杨醛诱导细胞死亡并增加线粒体活性氧（ROS）水平。我们发现，水杨醛和葡萄糖剥夺的这些作用与xCT（SLC7A11）的上调有关，xCT作为胱氨酸和谷氨酸的反向转运体，维持谷胱甘肽水平以维持氧化还原稳态。xCT的上调并未保护细胞免受氧化应激介导的细胞死亡，反而在葡萄糖剥夺期间促进了细胞死亡。此外，补充ROS清除剂N-乙酰半胱氨酸以及通过柳氮磺胺吡啶（xCT抑制剂）或二甲基-α-酮戊二酸维持细胞内氨基酸水平，可降低线粒体ROS水平并保护细胞免于死亡。我们的结果表明，水杨醛通过上调xCT和线粒体氧化应激增强葡萄糖剥夺期间的癌细胞死亡。
