GSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis

Abstract Ferroptosis is a newly characterized form of non-apoptotic-programmed cell death, which is driven by the lethal accumulation of iron-catalyzed lipid peroxides. Uncontrolled ferroptosis is implicated in the pathogenesis of a group of human diseases, while targeted induction of ferroptosis pr...

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Autores principales:	Lingjuan Wang, Sijin Ouyang, Bin Li, Hao Wu, Fengli Wang
Formato:	article
Lenguaje:	EN
Publicado:	Nature Publishing Group 2021
Materias:	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
Acceso en línea:	https://doaj.org/article/76208c12c0ba4889bc7bc358dddbcf06
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spelling	oai:doaj.org-article:76208c12c0ba4889bc7bc358dddbcf062021-11-07T12:21:14ZGSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis10.1038/s41420-021-00726-32058-7716https://doaj.org/article/76208c12c0ba4889bc7bc358dddbcf062021-11-01T00:00:00Zhttps://doi.org/10.1038/s41420-021-00726-3https://doaj.org/toc/2058-7716Abstract Ferroptosis is a newly characterized form of non-apoptotic-programmed cell death, which is driven by the lethal accumulation of iron-catalyzed lipid peroxides. Uncontrolled ferroptosis is implicated in the pathogenesis of a group of human diseases, while targeted induction of ferroptosis provides a potent therapeutic design for cancers. During the past decade, the fundamental regulatory circuits of ferroptosis have been identified. In this study, we show that the multifaceted Ser/Thr protein kinase GSK-3β acts as a positive modulator of the ferroptosis program. Pharmacological inhibition of GSK-3β by selective inhibitor LY2090314 or genetic KD of GSK-3β by shRNA potently promotes ferroptotic resistance. GSK-3β KD antagonizes the expression of iron metabolic components including DMT1, FTH1, and FTL, leading to the disruption of iron homeostasis and decline in intracellular labile free iron level. Taken together, our findings elaborate an indispensable role of GSK-3β in determining ferroptotic sensitivity by dominating cellular iron metabolism, which provides further insight into GSK-3β as a target for cancer chemotherapy.Lingjuan WangSijin OuyangBin LiHao WuFengli WangNature Publishing GrouparticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282CytologyQH573-671ENCell Death Discovery, Vol 7, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671
spellingShingle	Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Cytology QH573-671 Lingjuan Wang Sijin Ouyang Bin Li Hao Wu Fengli Wang GSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis
description	Abstract Ferroptosis is a newly characterized form of non-apoptotic-programmed cell death, which is driven by the lethal accumulation of iron-catalyzed lipid peroxides. Uncontrolled ferroptosis is implicated in the pathogenesis of a group of human diseases, while targeted induction of ferroptosis provides a potent therapeutic design for cancers. During the past decade, the fundamental regulatory circuits of ferroptosis have been identified. In this study, we show that the multifaceted Ser/Thr protein kinase GSK-3β acts as a positive modulator of the ferroptosis program. Pharmacological inhibition of GSK-3β by selective inhibitor LY2090314 or genetic KD of GSK-3β by shRNA potently promotes ferroptotic resistance. GSK-3β KD antagonizes the expression of iron metabolic components including DMT1, FTH1, and FTL, leading to the disruption of iron homeostasis and decline in intracellular labile free iron level. Taken together, our findings elaborate an indispensable role of GSK-3β in determining ferroptotic sensitivity by dominating cellular iron metabolism, which provides further insight into GSK-3β as a target for cancer chemotherapy.
format	article
author	Lingjuan Wang Sijin Ouyang Bin Li Hao Wu Fengli Wang
author_facet	Lingjuan Wang Sijin Ouyang Bin Li Hao Wu Fengli Wang
author_sort	Lingjuan Wang
title	GSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis
title_short	GSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis
title_full	GSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis
title_fullStr	GSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis
title_full_unstemmed	GSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis
title_sort	gsk-3β manipulates ferroptosis sensitivity by dominating iron homeostasis
publisher	Nature Publishing Group
publishDate	2021
url	https://doaj.org/article/76208c12c0ba4889bc7bc358dddbcf06
work_keys_str_mv	AT lingjuanwang gsk3bmanipulatesferroptosissensitivitybydominatingironhomeostasis AT sijinouyang gsk3bmanipulatesferroptosissensitivitybydominatingironhomeostasis AT binli gsk3bmanipulatesferroptosissensitivitybydominatingironhomeostasis AT haowu gsk3bmanipulatesferroptosissensitivitybydominatingironhomeostasis AT fengliwang gsk3bmanipulatesferroptosissensitivitybydominatingironhomeostasis
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GSK-3β manipulates ferroptosis sensitivity by dominating iron homeostasis

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