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Article

Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress

1
Department and Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
2
Division of Plastic and Reconstructive Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan
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Department of Surgery, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
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Department of Pharmacy, Taipei Veterans General Hospital, Taipei 112, Taiwan
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Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei 110, Taiwan
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Department of Dentistry, College of Dentistry, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
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Institute of Oral Biology, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
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Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
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Institute of Anatomy and Cell Biology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
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Comprehensive Breast Health Center, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan
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Department of Pharmacy, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
*
Authors to whom correspondence should be addressed.
Academic Editor: Jun Lu
Biomedicines 2021, 9(9), 1101; https://doi.org/10.3390/biomedicines9091101
Received: 19 July 2021 / Revised: 16 August 2021 / Accepted: 25 August 2021 / Published: 28 August 2021
(This article belongs to the Special Issue Mitochondrial Dysfunction and Oxidative Stress in Aging and Disease)
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. View Full-Text
Keywords: integrated stress response; salubrinal; oxidative stress; xCT integrated stress response; salubrinal; oxidative stress; xCT
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MDPI and ACS Style

Chen, M.-C.; Hsu, L.-L.; Wang, S.-F.; Pan, Y.-L.; Lo, J.-F.; Yeh, T.-S.; Tseng, L.-M.; Lee, H.-C. Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress. Biomedicines 2021, 9, 1101. https://doi.org/10.3390/biomedicines9091101

AMA Style

Chen M-C, Hsu L-L, Wang S-F, Pan Y-L, Lo J-F, Yeh T-S, Tseng L-M, Lee H-C. Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress. Biomedicines. 2021; 9(9):1101. https://doi.org/10.3390/biomedicines9091101

Chicago/Turabian Style

Chen, Mei-Chun, Li-Lin Hsu, Sheng-Fan Wang, Yi-Ling Pan, Jeng-Fan Lo, Tien-Shun Yeh, Ling-Ming Tseng, and Hsin-Chen Lee. 2021. "Salubrinal Enhances Cancer Cell Death during Glucose Deprivation through the Upregulation of xCT and Mitochondrial Oxidative Stress" Biomedicines 9, no. 9: 1101. https://doi.org/10.3390/biomedicines9091101

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