Elesclomol induces copper‐dependent ferroptosis in colorectal cancer cells via degradation of ATP7A

Cancer cells reprogram their copper metabolism to adapt to adverse microenvironments, such as oxidative stress. The copper chelator elesclomol has been reported to have considerable anticancer efficacy, but the underlying mechanisms remain largely unknown. In this study, we found that elesclomol‐med...

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Autores principales:	Wei Gao, Zhao Huang, Jiufei Duan, Edouard C. Nice, Jie Lin, Canhua Huang
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	ATP7A colorectal cancer copper elesclomol ferroptosis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/a004c29e4a7447ccb26c7e8b78992a28
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spelling	oai:doaj.org-article:a004c29e4a7447ccb26c7e8b78992a282021-12-02T10:31:06ZElesclomol induces copper‐dependent ferroptosis in colorectal cancer cells via degradation of ATP7A1878-02611574-789110.1002/1878-0261.13079https://doaj.org/article/a004c29e4a7447ccb26c7e8b78992a282021-12-01T00:00:00Zhttps://doi.org/10.1002/1878-0261.13079https://doaj.org/toc/1574-7891https://doaj.org/toc/1878-0261Cancer cells reprogram their copper metabolism to adapt to adverse microenvironments, such as oxidative stress. The copper chelator elesclomol has been reported to have considerable anticancer efficacy, but the underlying mechanisms remain largely unknown. In this study, we found that elesclomol‐mediated copper overload inhibits colorectal cancer (CRC) both in vitro and in vivo. Elesclomol alone promotes the degradation of the copper transporter copper‐transporting ATPase 1 (ATP7A), which retards the proliferation of CRC cells. This property distinguishes it from several other copper chelators. Combinational treatment of elesclomol and copper leads to copper retention within mitochondria due to ATP7A loss, leading to reactive oxygen species accumulation, which in turn promotes the degradation of SLC7A11, thus further enhancing oxidative stress and consequent ferroptosis in CRC cells. This effect accounts for the robust antitumour activity of elesclomol against CRC, which can be reversed by the administration of antioxidants and ferroptosis inhibitors, as well as the overexpression of ATP7A. In summary, our findings indicate that elesclomol‐induced copper chelation inhibits CRC by targeting ATP7A and regulating ferroptosis.Wei GaoZhao HuangJiufei DuanEdouard C. NiceJie LinCanhua HuangWileyarticleATP7Acolorectal cancercopperelesclomolferroptosisNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Oncology, Vol 15, Iss 12, Pp 3527-3544 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	ATP7A colorectal cancer copper elesclomol ferroptosis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	ATP7A colorectal cancer copper elesclomol ferroptosis Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Wei Gao Zhao Huang Jiufei Duan Edouard C. Nice Jie Lin Canhua Huang Elesclomol induces copper‐dependent ferroptosis in colorectal cancer cells via degradation of ATP7A
description	Cancer cells reprogram their copper metabolism to adapt to adverse microenvironments, such as oxidative stress. The copper chelator elesclomol has been reported to have considerable anticancer efficacy, but the underlying mechanisms remain largely unknown. In this study, we found that elesclomol‐mediated copper overload inhibits colorectal cancer (CRC) both in vitro and in vivo. Elesclomol alone promotes the degradation of the copper transporter copper‐transporting ATPase 1 (ATP7A), which retards the proliferation of CRC cells. This property distinguishes it from several other copper chelators. Combinational treatment of elesclomol and copper leads to copper retention within mitochondria due to ATP7A loss, leading to reactive oxygen species accumulation, which in turn promotes the degradation of SLC7A11, thus further enhancing oxidative stress and consequent ferroptosis in CRC cells. This effect accounts for the robust antitumour activity of elesclomol against CRC, which can be reversed by the administration of antioxidants and ferroptosis inhibitors, as well as the overexpression of ATP7A. In summary, our findings indicate that elesclomol‐induced copper chelation inhibits CRC by targeting ATP7A and regulating ferroptosis.
format	article
author	Wei Gao Zhao Huang Jiufei Duan Edouard C. Nice Jie Lin Canhua Huang
author_facet	Wei Gao Zhao Huang Jiufei Duan Edouard C. Nice Jie Lin Canhua Huang
author_sort	Wei Gao
title	Elesclomol induces copper‐dependent ferroptosis in colorectal cancer cells via degradation of ATP7A
title_short	Elesclomol induces copper‐dependent ferroptosis in colorectal cancer cells via degradation of ATP7A
title_full	Elesclomol induces copper‐dependent ferroptosis in colorectal cancer cells via degradation of ATP7A
title_fullStr	Elesclomol induces copper‐dependent ferroptosis in colorectal cancer cells via degradation of ATP7A
title_full_unstemmed	Elesclomol induces copper‐dependent ferroptosis in colorectal cancer cells via degradation of ATP7A
title_sort	elesclomol induces copper‐dependent ferroptosis in colorectal cancer cells via degradation of atp7a
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/a004c29e4a7447ccb26c7e8b78992a28
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Elesclomol induces copper‐dependent ferroptosis in colorectal cancer cells via degradation of ATP7A

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