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Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression

Ferroptosis has emerged to be a promising approach in cancer therapies; however, colorectal cancer (CRC) is relatively insensitive to ferroptosis. Exactly how the gut microenvironment impacts the ferroptotic sensitivity of CRC remains unknown. Herein, by performing metabolomics, we discovered that b...

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Autores principales: He, Ying, Ling, Yuhang, Zhang, Zhiyong, Mertens, Randall Tyler, Cao, Qian, Xu, Xutao, Guo, Ke, Shi, Qian, Zhang, Xilin, Huo, Lixia, Wang, Kan, Guo, Huihui, Shen, Weiyun, Shen, Manlu, Feng, Wenming, Xiao, Peng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10388208/
https://www.ncbi.nlm.nih.gov/pubmed/37494767
http://dx.doi.org/10.1016/j.redox.2023.102822
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author He, Ying
Ling, Yuhang
Zhang, Zhiyong
Mertens, Randall Tyler
Cao, Qian
Xu, Xutao
Guo, Ke
Shi, Qian
Zhang, Xilin
Huo, Lixia
Wang, Kan
Guo, Huihui
Shen, Weiyun
Shen, Manlu
Feng, Wenming
Xiao, Peng
author_facet He, Ying
Ling, Yuhang
Zhang, Zhiyong
Mertens, Randall Tyler
Cao, Qian
Xu, Xutao
Guo, Ke
Shi, Qian
Zhang, Xilin
Huo, Lixia
Wang, Kan
Guo, Huihui
Shen, Weiyun
Shen, Manlu
Feng, Wenming
Xiao, Peng
author_sort He, Ying
collection PubMed
description Ferroptosis has emerged to be a promising approach in cancer therapies; however, colorectal cancer (CRC) is relatively insensitive to ferroptosis. Exactly how the gut microenvironment impacts the ferroptotic sensitivity of CRC remains unknown. Herein, by performing metabolomics, we discovered that butyrate concentrations were significantly decreased in CRC patients. Butyrate supplementation sensitized CRC mice to ferroptosis induction, showing great in vivo translatability. Particularly, butyrate treatment reduced ferroptotic resistance of cancer stem cells. Mechanistically, butyrate inhibited xCT expression and xCT-dependent glutathione synthesis. Moreover, we identified c-Fos as a novel xCT suppressor, and further elucidated that butyrate induced c-Fos expression via disrupting class I HDAC activity. In CRC patients, butyrate negatively correlated with tumor xCT expression and positively correlated with c-Fos expression. Finally, butyrate was found to boost the pro-ferroptotic function of oxaliplatin (OXA). Immunohistochemistry data showed that OXA non-responders exhibited higher xCT expression compared to OXA responders. Hence, butyrate supplementation is a promising approach to break the ferroptosis resistance in CRC.
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spelling pubmed-103882082023-08-01 Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression He, Ying Ling, Yuhang Zhang, Zhiyong Mertens, Randall Tyler Cao, Qian Xu, Xutao Guo, Ke Shi, Qian Zhang, Xilin Huo, Lixia Wang, Kan Guo, Huihui Shen, Weiyun Shen, Manlu Feng, Wenming Xiao, Peng Redox Biol Research Paper Ferroptosis has emerged to be a promising approach in cancer therapies; however, colorectal cancer (CRC) is relatively insensitive to ferroptosis. Exactly how the gut microenvironment impacts the ferroptotic sensitivity of CRC remains unknown. Herein, by performing metabolomics, we discovered that butyrate concentrations were significantly decreased in CRC patients. Butyrate supplementation sensitized CRC mice to ferroptosis induction, showing great in vivo translatability. Particularly, butyrate treatment reduced ferroptotic resistance of cancer stem cells. Mechanistically, butyrate inhibited xCT expression and xCT-dependent glutathione synthesis. Moreover, we identified c-Fos as a novel xCT suppressor, and further elucidated that butyrate induced c-Fos expression via disrupting class I HDAC activity. In CRC patients, butyrate negatively correlated with tumor xCT expression and positively correlated with c-Fos expression. Finally, butyrate was found to boost the pro-ferroptotic function of oxaliplatin (OXA). Immunohistochemistry data showed that OXA non-responders exhibited higher xCT expression compared to OXA responders. Hence, butyrate supplementation is a promising approach to break the ferroptosis resistance in CRC. Elsevier 2023-07-20 /pmc/articles/PMC10388208/ /pubmed/37494767 http://dx.doi.org/10.1016/j.redox.2023.102822 Text en © 2023 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Paper
He, Ying
Ling, Yuhang
Zhang, Zhiyong
Mertens, Randall Tyler
Cao, Qian
Xu, Xutao
Guo, Ke
Shi, Qian
Zhang, Xilin
Huo, Lixia
Wang, Kan
Guo, Huihui
Shen, Weiyun
Shen, Manlu
Feng, Wenming
Xiao, Peng
Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression
title Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression
title_full Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression
title_fullStr Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression
title_full_unstemmed Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression
title_short Butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-Fos-dependent xCT suppression
title_sort butyrate reverses ferroptosis resistance in colorectal cancer by inducing c-fos-dependent xct suppression
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10388208/
https://www.ncbi.nlm.nih.gov/pubmed/37494767
http://dx.doi.org/10.1016/j.redox.2023.102822
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