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

Autor: Miao Z; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.; Department of Neurosurgery, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai, China., Tian W; Department of Neurosurgery, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, China., Ye Y; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Gu W; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Bao Z; Department of Neurosurgery, The Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, Wuxi, China., Xu L; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Sun G; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Li C; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Tu Y; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Chao H; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China., Lam SM; LipidALL Technologies Company Limited, Changzhou, China., Liu N; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. liuning0853@126.com., Ji J; Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China. jijing@njmu.edu.cn.; Institute for Brain Tumors, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China. jijing@njmu.edu.cn.; Gusu School, Nanjing Medical University, Suzhou, China. jijing@njmu.edu.cn.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2022 Jun 13; Vol. 13 (6), pp. 548. Date of Electronic Publication: 2022 Jun 13.
DOI: 10.1038/s41419-022-04997-1
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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