2. Academic Validation
  3. Reciprocal regulation between RACGAP1 and AR contributes to endocrine therapy resistance in prostate cancer

Reciprocal regulation between RACGAP1 and AR contributes to endocrine therapy resistance in prostate cancer

  • Cell Commun Signal. 2024 Jun 19;22(1):339. doi: 10.1186/s12964-024-01703-w.
Jiajia Wang 1,  Hui Liu 2,  Zeyuan Yu 1,  Qianqian Zhou 1,  Feifei Sun 2,  Jingying Han 1,  Lin Gao 1,  Baokai Dou 3,  Hanwen Zhang 1,  Jiawei Fu 1,  Wenqiao Jia 2,  Weiwen Chen 4,  Jing Hu 5 6,  Bo Han 7 8
Affiliations

Affiliations

  • 1 The Key Laboratory of Experimental Teratology, Department of Pathology, School of Basic Medical Sciences, Ministry of Education, Shandong University, Jinan, 250012, Shandong, China.
  • 2 Department of Pathology, Qilu Hospital, Shandong University, Jinan, 250012, China.
  • 3 Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 4 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China.
  • 5 Department of Pathology, Qilu Hospital, Shandong University, Jinan, 250012, China. jinga@umich.edu.
  • 6 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. jinga@umich.edu.
  • 7 The Key Laboratory of Experimental Teratology, Department of Pathology, School of Basic Medical Sciences, Ministry of Education, Shandong University, Jinan, 250012, Shandong, China. boh@sdu.edu.cn.
  • 8 Department of Pathology, Qilu Hospital, Shandong University, Jinan, 250012, China. boh@sdu.edu.cn.
PMID: 38898473 DOI: 10.1186/s12964-024-01703-w
Abstract

Background: Endocrine resistance driven by sustained activation of Androgen Receptor (AR) signaling pathway in advanced prostate Cancer (PCa) is fatal. Characterization of mechanisms underlying aberrant AR pathway activation to search for potential therapeutic strategy is particularly important. Rac GTPase-activating protein 1 (RACGAP1) is one of the specific GTPase-activating proteins. As a novel tumor proto-oncogene, overexpression of RACGAP1 was related to the occurrence of various tumors.

Methods: Bioinformatics methods were used to analyze the relationship of expression level between RACGAP1 and AR as well as AR pathway activation. qRT-PCR and western blotting assays were performed to assess the expression of AR/AR-V7 and RACGAP1 in PCa cells. Immunoprecipitation and immunofluorescence experiments were conducted to detect the interaction and co-localization between RACGAP1 and AR/AR-V7. Gain- and loss-of-function analyses were conducted to investigate the biological roles of RACGAP1 in PCa cells, using MTS and colony formation assays. In vivo experiments were conducted to evaluate the effect of RACGAP1 inhibition on the tumor growth.

Results: RACGAP1 was a gene activated by AR, which was markedly upregulated in PCa patients with CRPC and enzalutamide resistance. AR transcriptionally activated RACGAP1 expression by binding to its promoter region. Reciprocally, nuclear RACGAP1 bound to the N-terminal domain (NTD) of both AR and AR-V7, blocking their interaction with the E3 ubiquitin Ligase MDM2. Consequently, this prevented the degradation of AR/AR-V7 in a ubiquitin-proteasome-dependent pathway. Notably, the positive feedback loop between RACGAP1 and AR/AR-V7 contributed to endocrine therapy resistance of CRPC. Combination of enzalutamide and in vivo cholesterol-conjugated RIG-I siRNA drugs targeting RACGAP1 induced potent inhibition of xenograft tumor growth of PCa.

Conclusion: In summary, our results reveal that reciprocal regulation between RACGAP1 and AR/AR-V7 contributes to the endocrine resistance in PCa. These findings highlight the therapeutic potential of combined RACGAP1 inhibition and enzalutamide in treatment of advanced PCa.

Keywords

AR; AR-V7; CRPC; Endocrine therapy resistance; MDM2; RACGAP1.

Figures
Products