Role of the DEAD-box RNA helicase DDX5 (p68) in cancer DNA repair, immune suppression, cancer metabolic control, virus infection promotion, and human microbiome (microbiota) negative influence

Journal of Experimental & Clinical Cancer Research

Review

Jianmin Wang¹  Pawel Kalinski²  Xiaozhuo Liu³  Anmbreen Jamroze³  Xiang Ling⁴  Dean G. Tang⁵  Sayan Chakraborty⁵  Fengzhi Li⁵  Christos Fountzilas⁶ 

[1] Department of Bioinformatics & Biostatistics, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, NY, USA;Department of Immunology, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, NY, USA;Program of Tumor Immunology & Immunotherapy, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, NY, USA;Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, 14263, Buffalo, NY, USA;Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, 14263, Buffalo, NY, USA;Canget BioTekpharma LLC, 14203, Buffalo, NY, USA;Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Elm and Carlton Streets, 14263, Buffalo, NY, USA;Program of Developmental Therapeutics, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, NY, USA;Program of Developmental Therapeutics, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, NY, USA;Department of Medicine, Roswell Park Comprehensive Cancer Center, 14263, Buffalo, NY, USA;

关键词: DDX5;    p68;    DNA repair;    Immune suppression;    Virus infection promotion;    Cancer metabolic control;    Microbiota negative influence;    Oncotarget;    Cancer therapeutics;    DDX5 degrader FL118;   

DOI  :  10.1186/s13046-023-02787-x

 received in 2023-06-20, accepted in 2023-08-01,  发布年份 2023

来源: Springer

【 摘 要 】

There is increasing evidence indicating the significant role of DDX5 (also called p68), acting as a master regulator and a potential biomarker and target, in tumorigenesis, proliferation, metastasis and treatment resistance for cancer therapy. However, DDX5 has also been reported to act as an oncosuppressor. These seemingly contradictory observations can be reconciled by DDX5’s role in DNA repair. This is because cancer cell apoptosis and malignant transformation can represent the two possible outcomes of a single process regulated by DDX5, reflecting different intensity of DNA damage. Thus, targeting DDX5 could potentially shift cancer cells from a growth-arrested state (necessary for DNA repair) to apoptosis and cell killing. In addition to the increasingly recognized role of DDX5 in global genome stability surveillance and DNA damage repair, DDX5 has been implicated in multiple oncogenic signaling pathways. DDX5 appears to utilize distinct signaling cascades via interactions with unique proteins in different types of tissues/cells to elicit opposing roles (e.g., smooth muscle cells versus cancer cells). Such unique features make DDX5 an intriguing therapeutic target for the treatment of human cancers, with limited low toxicity to normal tissues. In this review, we discuss the multifaceted functions of DDX5 in DNA repair in cancer, immune suppression, oncogenic metabolic rewiring, virus infection promotion, and negative impact on the human microbiome (microbiota). We also provide new data showing that FL118, a molecular glue DDX5 degrader, selectively works against current treatment-resistant prostate cancer organoids/cells. Altogether, current studies demonstrate that DDX5 may represent a unique oncotarget for effectively conquering cancer with minimal toxicity to normal tissues.

【 授权许可】

CC BY   
© Italian National Cancer Institute ‘Regina Elena’ 2023

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