Retinoblastoma-associated protein is important for TRIM24-mediated activation of the mTOR signaling pathway through DUSP2 action in prostate cancer.

Autor: Ren D; Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.; Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China., Li W; Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.; Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China., Zeng R; Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.; Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China., Liu X; Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.; Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China., Liang H; Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.; Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China., Xiong W; Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.; Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China., Yang C; Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. cgyang-hust@hotmail.com., Jin X; Department of Urology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China. jinxinxy2@csu.edu.cn.; Uro-Oncology Institute of Central South University, Changsha, Hunan, 410011, China. jinxinxy2@csu.edu.cn.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2024 May; Vol. 31 (5), pp. 592-604. Date of Electronic Publication: 2024 Mar 21.
DOI: 10.1038/s41418-024-01282-w
Abstrakt: RB transcriptional corepressor 1 (RB) deletion is the most important genomic factor associated with the prognosis of castration-resistant prostate cancer (CRPC) patients receiving androgen receptor (AR) signaling inhibitor therapy. Loss of RB could support prostate cancer cell growth in a hormone-independent manner, but the underlying mechanism by which RB regulates tumor progression extends far beyond the cell cycle pathway. A previous study indicated that RB inactivates AKT signaling but has no effect on mTOR signaling in cancer cells. Here, we found that the S249/T252 site in RB is key to regulating the transcriptional activity of the tumor-promoting factor TRIM24 in CRPC, as identified through FXXXV mapping. The RB/TRIM24 complex functions through DUSP2, which serves as an intermediate bridge, to activate the mTOR pathway and promote prostate cancer progression. Accordingly, we designed RB-linker-proteolysis-targeting chimera (PROTAC) molecules, which decreased TRIM24 protein levels and inactivated the mTOR signaling pathway, thereby inhibiting prostate cancer. Therefore, this study not only elucidates the novel function of RB but also provides a theoretical basis for the development of new drugs for treating prostate cancer.
(© 2024. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)
Databáze: MEDLINE
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