Protein degradation: expanding the toolbox to restrain cancer drug resistance

Journal of Hematology & Oncology

Review

Edouard C. Nice¹  Tingyuan Lang²  Weifeng He³  Bowen Li⁴  Hui Ming⁴  Siyuan Qin⁴  Jingwen Jiang⁴  Canhua Huang⁴ 

[1]Department of Biochemistry and Molecular Biology, Monash University, 3800, Clayton, VIC, Australia

[2]Department of Gynecologic Oncology, Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital, 400030, Chongqing, People’s Republic of China

[3]Reproductive Medicine Center, The First Affiliated Hospital of Chongqing Medical University, 400042, Chongqing, People’s Republic of China

[4]Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Army Military Medical University, 400038, Chongqing, China

[5]West China School of Basic Medical Sciences and Forensic Medicine, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, People’s Republic of China

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

DOI  :  10.1186/s13045-023-01398-5

 received in 2022-09-24, accepted in 2023-01-01,  发布年份 2023

来源: Springer

【 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.

【 授权许可】

CC BY   
© The Author(s) 2023

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