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ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation

xCT, also known as solute carrier family 7 member 11 (SLC7A11), the light chain of the cystine/glutamate antiporter, is positively correlated with cancer progression due to antioxidant function. During glucose deprivation, the overexpression of xCT does not protect cancer cells but instead promotes...

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Autores principales: Chen, Mei-Chun, Hsu, Li-Lin, Wang, Sheng-Fan, Hsu, Chih-Yi, Lee, Hsin-Chen, Tseng, Ling-Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407809/
https://www.ncbi.nlm.nih.gov/pubmed/32630312
http://dx.doi.org/10.3390/cells9071598
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author Chen, Mei-Chun
Hsu, Li-Lin
Wang, Sheng-Fan
Hsu, Chih-Yi
Lee, Hsin-Chen
Tseng, Ling-Ming
author_facet Chen, Mei-Chun
Hsu, Li-Lin
Wang, Sheng-Fan
Hsu, Chih-Yi
Lee, Hsin-Chen
Tseng, Ling-Ming
author_sort Chen, Mei-Chun
collection PubMed
description xCT, also known as solute carrier family 7 member 11 (SLC7A11), the light chain of the cystine/glutamate antiporter, is positively correlated with cancer progression due to antioxidant function. During glucose deprivation, the overexpression of xCT does not protect cancer cells but instead promotes cell death. Further understanding the mechanism of glucose deprivation-induced cell death is important for developing anticancer treatments targeting the glucose metabolism. In this study, we found that breast cancer cells with a high expression of xCT demonstrated increased levels of reactive oxygen species (ROS) and were more sensitive to glucose deprivation than the cells with a low expression of xCT. However, AMP-activated protein kinase (AMPK) did not significantly affect glucose-deprivation-induced cell death. The antioxidant N-acetyl-cysteine prevented glucose-deprivation-induced cell death, and the glutathione biosynthesis inhibitor L-buthionine-S, R-sulfoximine enhanced glucose-deprivation-induced cell death. The inhibition of xCT by sulfasalazine or a knockdown of xCT reduced the glucose-deprivation-increased ROS levels and glucose-deprivation-induced cell death. Glucose deprivation reduced the intracellular glutamate, and supplementation with α-ketoglutarate prevented the glucose-deprivation-increased ROS levels and rescued cell death. The knockdown of sirtuin-3 (SIRT3) further enhanced the ROS levels, and promoted xCT-related cell death after glucose deprivation. In conclusion, our results suggested that ROS play a critical role in xCT-dependent cell death in breast cancer cells under glucose deprivation.
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spelling pubmed-74078092020-08-12 ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation Chen, Mei-Chun Hsu, Li-Lin Wang, Sheng-Fan Hsu, Chih-Yi Lee, Hsin-Chen Tseng, Ling-Ming Cells Article xCT, also known as solute carrier family 7 member 11 (SLC7A11), the light chain of the cystine/glutamate antiporter, is positively correlated with cancer progression due to antioxidant function. During glucose deprivation, the overexpression of xCT does not protect cancer cells but instead promotes cell death. Further understanding the mechanism of glucose deprivation-induced cell death is important for developing anticancer treatments targeting the glucose metabolism. In this study, we found that breast cancer cells with a high expression of xCT demonstrated increased levels of reactive oxygen species (ROS) and were more sensitive to glucose deprivation than the cells with a low expression of xCT. However, AMP-activated protein kinase (AMPK) did not significantly affect glucose-deprivation-induced cell death. The antioxidant N-acetyl-cysteine prevented glucose-deprivation-induced cell death, and the glutathione biosynthesis inhibitor L-buthionine-S, R-sulfoximine enhanced glucose-deprivation-induced cell death. The inhibition of xCT by sulfasalazine or a knockdown of xCT reduced the glucose-deprivation-increased ROS levels and glucose-deprivation-induced cell death. Glucose deprivation reduced the intracellular glutamate, and supplementation with α-ketoglutarate prevented the glucose-deprivation-increased ROS levels and rescued cell death. The knockdown of sirtuin-3 (SIRT3) further enhanced the ROS levels, and promoted xCT-related cell death after glucose deprivation. In conclusion, our results suggested that ROS play a critical role in xCT-dependent cell death in breast cancer cells under glucose deprivation. MDPI 2020-07-01 /pmc/articles/PMC7407809/ /pubmed/32630312 http://dx.doi.org/10.3390/cells9071598 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Mei-Chun
Hsu, Li-Lin
Wang, Sheng-Fan
Hsu, Chih-Yi
Lee, Hsin-Chen
Tseng, Ling-Ming
ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation
title ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation
title_full ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation
title_fullStr ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation
title_full_unstemmed ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation
title_short ROS Mediate xCT-Dependent Cell Death in Human Breast Cancer Cells under Glucose Deprivation
title_sort ros mediate xct-dependent cell death in human breast cancer cells under glucose deprivation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407809/
https://www.ncbi.nlm.nih.gov/pubmed/32630312
http://dx.doi.org/10.3390/cells9071598
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