Bcl-xL regulates radiation-induced ferroptosis through chaperone-mediated autophagy of GPX4 in tumor cells  

作　　者：Jing Han Ruru Wang Bin Chen Feng Xu Liangchen Wei An Xu Lijun Wu Guoping Zhao 

机构地区：[1]High Magnetic Field Laboratory,Key Laboratory of High Magnetic Field and Ion Beam Physical Biology,Chinese Academy of Sciences,Anhui Province Key Laboratory of Environmental Toxicology and Pollution Control Technology,Hefei Institutes of Physical Science,Anhui 230031,China [2]University of Science and Technology of China,Hefei 230026,China [3]School of Public Health,Wannan Medical College,Wuhu 241002,China

出　　处：《Radiation Medicine and Protection》2024年第2期90-99,共10页放射医学与防护（英文）

基　　金：the National Science Fund for Excellent Young Scholars(grant number 12122510);the National Natural Science Foundation of China(grant number 32171240);Anhui Provincial Natural Science Foundation(grant numbers 2108085MH279);the HFIPS Director’s Fund(grant numbers BJPY2021B07 and BJPY2023A010).

摘　　要：Objective:To investigate the role and the molecular mechanisms of apoptotic signaling in ferroptosis to regulate tumor radiosensitivity.Methods:Reactive oxygen species(ROS)and lipid peroxide levels were detected in Mouse embryonic fibroblasts(MEFs)with Bcl-xL or Mcl-1 deficiency induced by erastin.Colony formation,ROS,lipid peroxidation and the transcription/translation levels of PTGS2 were measured in Bcl-xL knockdown tumor cells induced by 5 Gyγ-rays or co-treated with ferrostatin-1(Ferr-1).The protein levels of LPCAT3,ACSL4 and PEBP1 in Bcl-xL knockout MEF cells were evaluated in Bcl-xL knockout MEF cells post-radiation.Moreover,the interaction of heat shock protein 90(HSP90)with Bcl-xL,GPX4,or LAMP2A was detected by protein mass spectrometry and immunoprecipitation assays.Results:Manipulating Bcl-xL levels facilitated radiation-induced ferroptosis by augmenting the enzymatic oxidation of polyunsaturated fatty acids(PUFAs)and enhancing chaperone-mediated autophagy(CMA)of glutathione peroxidase 4(GPX4)(MEF cell line:t=4.540,P<0.01;A549 cell line:t=56.16,P<0.0001;t=4.885,P<0.01;HCT116 cell line:t=14.75,P<0.01;t=7.363,P<0.05).Downregulating Bcl-xL expression promoted the activity of acyl-CoA synthetase long-chain family member 4(ACSL4),thus increasing the enzymatic oxidation of PUFAs(t=4.258,P<0.01).Moreover,depletion of Bcl-xL expedited the CMA process targeting GPX4 by facilitating the association of GPX4 with heat shock protein 90(HSP90)and LAMP2A following radiation exposure.Subsequent degradation of GPX4 led to the accumulation of lipid peroxides,ultimately triggering ferroptosis.Conclusions:Our study provides initial insights into the regulatory role of Bcl-xL in ferroptosis and underscores the potential of targeting Bcl-xL as a promising therapeutic strategy for cancer by modulating both apoptotic and ferroptotic pathways.

关 键 词：BCL-XL Ferroptosis GPX4 Chaperone-mediated autophagy Lipid peroxidation 

分 类 号：R730[医药卫生—肿瘤]