Hsp90 induces Acsl4-dependent glioma ferroptosis via dephosphorylating Ser637 at Drp1

Ferroptosis is a newly identified form of regulated cell death (RCD) characterized by the iron-dependent lipid reactive oxygen species (ROS) accumulation, but its mechanism in gliomas remains elusive. Acyl–coenzyme A (CoA) synthetase long-chain family member 4 (Acsl4), a pivotal enzyme in the regula...

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Published in:Cell death & disease 2022-06, Vol.13 (6), p.548-548, Article 548
Main Authors: Miao, Zong, Tian, Wei, Ye, Yangfan, Gu, Wei, Bao, Zhongyuan, Xu, Lei, Sun, Guangchi, Li, Chong, Tu, Yiming, Chao, Honglu, Lam, Sin Man, Liu, Ning, Ji, Jing
Format: Article
Language:English
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Antibodies
Antitumor activity
Biochemistry
Biomedical and Life Sciences
Calcineurin
Cell Biology
Cell Culture
Cell death
Coenzyme A
Coenzyme A Ligases - genetics
Coenzyme A Ligases - metabolism
Dephosphorylation
Dynamin
Dynamins
Ferroptosis
Glioma
Glioma - genetics
Glutathione peroxidase
Heat shock proteins
Hsp90 protein
Humans
Immunology
Life Sciences
Lipid peroxidation
Lipids
Mitochondria
Reactive oxygen species
Serine
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Summary:Ferroptosis is a newly identified form of regulated cell death (RCD) characterized by the iron-dependent lipid reactive oxygen species (ROS) accumulation, but its mechanism in gliomas remains elusive. Acyl–coenzyme A (CoA) synthetase long-chain family member 4 (Acsl4), a pivotal enzyme in the regulation of lipid biosynthesis, benefits the initiation of ferroptosis, but its role in gliomas needs further clarification. Erastin, a classic inducer of ferroptosis, has recently been found to regulate lipid peroxidation by regulating Acsl4 other than glutathione peroxidase 4 (GPX4) in ferroptosis. In this study, we demonstrated that heat shock protein 90 (Hsp90) and dynamin-related protein 1 (Drp1) actively regulated and stabilized Acsl4 expression in erastin-induced ferroptosis in gliomas. Hsp90 overexpression and calcineurin (CN)–mediated Drp1 dephosphorylation at serine 637 (Ser637) promoted ferroptosis by altering mitochondrial morphology and increasing Acsl4-mediated lipid peroxidation. Importantly, promotion of the Hsp90–Acsl4 pathway augmented anticancer activity of erastin in vitro and in vivo. Our discovery reveals a novel and efficient approach to ferroptosis-mediated glioma therapy.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-022-04997-1