Targeting PHB1 to inhibit castration-resistant prostate cancer progression in vitro and in vivo

Journal of Experimental & Clinical Cancer Research

Research

Junmei Liu¹  Weiwen Chen¹  Ruixi Qin²  Jian Zhao³  Laurent Désaubry⁴  Yuanxin Xing⁵  Jingying Han⁶  Qianqian Zhou⁷  Wenjie Cai⁷  Lin Gao⁷  Feifei Sun⁷  Ranran Zhang⁷  Xinpei Wang⁷  Zongyue He⁷  Xin Wang⁷  Tong Su⁷  Bo Han⁸ 

[1] Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China;Department of Pathology, Qilu Hospital of Shandong University, Jinan, China;Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan, China;INSERM, UMR 1260, Regenerative Nanomedicine, University of Strasbourg, FMTS (Fédération de Médecine Translationnelle de L’Université de Strasbourg), Strasbourg, France;Research Center of Basic Medicine, Jinan Central Hospital, Shandong First Medical University, Jinan, China;School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China;The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China;The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China;Department of Pathology, Qilu Hospital of Shandong University, Jinan, China;

关键词: CRPC;    Prohibitin;    FL3;    Enzalutamide;   

DOI  :  10.1186/s13046-023-02695-0

 received in 2022-11-30, accepted in 2023-05-01,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundCastration-resistant prostate cancer (CRPC) is currently the main challenge for prostate cancer (PCa) treatment, and there is an urgent need to find novel therapeutic targets and drugs. Prohibitin (PHB1) is a multifunctional chaperone/scaffold protein that is upregulated in various cancers and plays a pro-cancer role. FL3 is a synthetic flavagline drug that inhibits cancer cell proliferation by targeting PHB1. However, the biological functions of PHB1 in CRPC and the effect of FL3 on CRPC cells remain to be explored.MethodsSeveral public datasets were used to analyze the association between the expression level of PHB1 and PCa progression as well as outcome in PCa patients. The expression of PHB1 in human PCa specimens and PCa cell lines was examined by immunohistochemistry (IHC), qRT-PCR, and Western blot. The biological roles of PHB1 in castration resistance and underlying mechanisms were investigated by gain/loss-of-function analyses. Next, in vitro and in vivo experiments were conducted to investigate the anti-cancer effects of FL3 on CRPC cells as well as the underlying mechanisms.ResultsPHB1 expression was significantly upregulated in CRPC and was associated with poor prognosis. PHB1 promoted castration resistance of PCa cells under androgen deprivation condition. PHB1 is an androgen receptor (AR) suppressive gene, and androgen deprivation promoted the PHB1 expression and its nucleus-cytoplasmic translocation. FL3, alone or combined with the second-generation anti-androgen Enzalutamide (ENZ), suppressed CRPC cells especially ENZ-sensitive CRPC cells both in vitro and in vivo. Mechanically, we demonstrated that FL3 promoted trafficking of PHB1 from plasma membrane and mitochondria to nucleus, which in turn inhibited AR signaling as well as MAPK signaling, yet promoted apoptosis in CRPC cells.ConclusionOur data indicated that PHB1 is aberrantly upregulated in CRPC and is involved in castration resistance, as well as providing a novel rational approach for treating ENZ-sensitive CRPC.

【 授权许可】

CC BY   
© The Author(s) 2023

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