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DNAJC12 causes breast cancer chemotherapy resistance by repressing doxorubicin-induced ferroptosis and apoptosis via activation of AKT

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资源类型：
Pubmed体系：
作者：
Shen Mengjia[1,2] ; Cao Shiyu[2] ; Long Xinyi[2] ; Xiao Lin[2] ; Yang Libo[1,2] ; Zhang Peichuan[4] ; Li Li[2] ; Chen Fei[2] ; Lei Ting[5] ; Gao Hongwei[6] ; Ye Feng[2,3,*1] ; Bu Hong[1,2,3,*1] ;
机构： [1]Department of Pathology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan, China [2]Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China [3]Key Lab of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China [4]Institute of Thoracic Oncology and Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China [5]Department of Pathology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu 213003, China [6]Laboratory Medicine Center, Lanzhou University Second Hospital, The Second Clinical Medical College of Lanzhou University, Lanzhou 730000, China
出处：
DOI： 10.1016/j.redox.2024.103035

关键词： DNAJC12 Breast cancer HSP70 AKT Ferroptosis Apoptosis

摘要：
Chemotherapy is a primary treatment for breast cancer (BC), yet many patients develop resistance over time. This study aims to identify critical factors contributing to chemoresistance and their underlying molecular mechanisms, with a focus on reversing this resistance.We utilized samples from the Gene Expression Omnibus (GEO) and West China Hospital to identify and validate genes associated with chemoresistance. Functional studies were conducted using MDA-MB-231 and MCF-7 cell lines, involving gain-of-function and loss-of-function approaches. RNA sequencing (RNA-seq) identified potential mechanisms. We examined interactions between DNAJC12, HSP70, and AKT using co-immunoprecipitation (Co-IP) assays and established cell line-derived xenograft (CDX) models for in vivo validations.Boruta analysis of four GEO datasets identified DNAJC12 as highly significant. Patients with high DNAJC12 expression showed an 8 % pathological complete response (pCR) rate, compared to 38 % in the low expression group. DNAJC12 inhibited doxorubicin (DOX)-induced cell death through both ferroptosis and apoptosis. Combining apoptosis and ferroptosis inhibitors completely reversed DOX resistance caused by DNAJC12 overexpression. RNA-seq suggested that DNAJC12 overexpression activated the PI3K-AKT pathway. Inhibition of AKT reversed the DOX resistance induced by DNAJC12, including reduced apoptosis and ferroptosis, restoration of cleaved caspase 3, and decreased GPX4 and SLC7A11 levels. Additionally, DNAJC12 was found to increase AKT phosphorylation in an HSP70-dependent manner, and inhibiting HSP70 also reversed the DOX resistance. In vivo studies confirmed that AKT inhibition reversed DNAJC12-induced DOX resistance in the CDX model.DNAJC12 expression is closely linked to chemoresistance in BC. The DNAJC12-HSP70-AKT signaling axis is crucial in mediating resistance to chemotherapy by suppressing DOX-induced ferroptosis and apoptosis. Our findings suggest that targeting AKT and HSP70 activities may offer new therapeutic strategies to overcome chemoresistance in BC.Copyright © 2024 West China Hospital, Sichuan University, China. Published by Elsevier B.V. All rights reserved.

基金：
The work was supported by the 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD18012, ZYJC21035, ZYGX2022YGRH015).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2023]版：
大类 | 1 区 生物学
小类 | 1 区 生化与分子生物学
最新[2023]版：
大类 | 1 区 生物学
小类 | 1 区 生化与分子生物学
第一作者：
第一作者机构： [1]Department of Pathology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan, China [2]Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
通讯作者：
通讯机构： [1]Department of Pathology, West China Hospital, Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, Sichuan, China [2]Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China [3]Key Lab of Transplant Engineering and Immunology, Ministry of Health, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China [*1]Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
推荐引用方式(GB/T 7714)：
Shen Mengjia,Cao Shiyu,Long Xinyi,et al.DNAJC12 causes breast cancer chemotherapy resistance by repressing doxorubicin-induced ferroptosis and apoptosis via activation of AKT[J].Redox Biology.2024,70:103035.doi:10.1016/j.redox.2024.103035.
APA：
Shen Mengjia,Cao Shiyu,Long Xinyi,Xiao Lin,Yang Libo...&Bu Hong.(2024).DNAJC12 causes breast cancer chemotherapy resistance by repressing doxorubicin-induced ferroptosis and apoptosis via activation of AKT.Redox Biology,70,
MLA：
Shen Mengjia,et al."DNAJC12 causes breast cancer chemotherapy resistance by repressing doxorubicin-induced ferroptosis and apoptosis via activation of AKT".Redox Biology 70.(2024):103035

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