Protein degradation: expanding the toolbox to restrain cancer drug resistance

作者全名："Ming, Hui; Li, Bowen; Jiang, Jingwen; Qin, Siyuan; Nice, Edouard C.; He, Weifeng; Lang, Tingyuan; Huang, Canhua"

作者地址："[Ming, Hui; Li, Bowen; Jiang, Jingwen; Qin, Siyuan; Huang, Canhua] Sichuan Univ, West China Hosp, West China Sch Basic Med Sci & Forens Med, Chengdu 610041, Peoples R China; [Ming, Hui; Li, Bowen; Jiang, Jingwen; Qin, Siyuan; Huang, Canhua] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China; [Ming, Hui; Li, Bowen; Jiang, Jingwen; Qin, Siyuan; Huang, Canhua] Sichuan Univ, West China Hosp, Canc Ctr, Chengdu 610041, Peoples R China; [Ming, Hui; Li, Bowen; Jiang, Jingwen; Qin, Siyuan; Huang, Canhua] Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China; [Nice, Edouard C.] Monash Univ, Dept Biochem & Mol Biol, Clayton, Vic 3800, Australia; [He, Weifeng] Army Mil Med Univ, Southwest Hosp, Inst Burn Res, State Key Lab Trauma Burn & Combined Injury,Chongq, Chongqing 400038, Peoples R China; [Lang, Tingyuan] Chongqing Univ, Canc Hosp, Dept Gynecol Oncol, Chongqing 400030, Peoples R China; [Lang, Tingyuan] Chongqing Canc Inst, Chongqing 400030, Peoples R China; [Lang, Tingyuan] Chongqing Canc Hosp, Chongqing 400030, Peoples R China; [Lang, Tingyuan] Chongqing Med Univ, Affiliated Hosp 1, Reprod Med Ctr, Chongqing 400042, Peoples R China"

通信作者："Huang, CH (通讯作者)，Sichuan Univ, West China Hosp, West China Sch Basic Med Sci & Forens Med, Chengdu 610041, Peoples R China.; Huang, CH (通讯作者)，Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China.; Huang, CH (通讯作者)，Sichuan Univ, West China Hosp, Canc Ctr, Chengdu 610041, Peoples R China.; Huang, CH (通讯作者)，Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Peoples R China.; He, WF (通讯作者)，Army Mil Med Univ, Southwest Hosp, Inst Burn Res, State Key Lab Trauma Burn & Combined Injury,Chongq, Chongqing 400038, Peoples R China.; Lang, TY (通讯作者)，Chongqing Univ, Canc Hosp, Dept Gynecol Oncol, Chongqing 400030, Peoples R China.; Lang, TY (通讯作者)，Chongqing Canc Inst, Chongqing 400030, Peoples R China.; Lang, TY (通讯作者)，Chongqing Canc Hosp, Chongqing 400030, Peoples R China.; Lang, TY (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Reprod Med Ctr, Chongqing 400042, Peoples R China."

来源：JOURNAL OF HEMATOLOGY & ONCOLOGY

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:000922265400001

JCR分区：Q1

影响因子：29.5

年份：2023

卷号：16

期号：1

开始页：　

结束页：　

文献类型：Review

关键词：E3 ligase; DUBs; Chaperone-mediated autophagy; Protein degradation; Drug resistance

摘要："Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies."

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