2. Academic Validation
  3. RUVBL1 promotes enzalutamide resistance of prostate tumors through the PLXNA1-CRAF-MAPK pathway

RUVBL1 promotes enzalutamide resistance of prostate tumors through the PLXNA1-CRAF-MAPK pathway

  • Oncogene. 2022 Jun;41(23):3239-3250. doi: 10.1038/s41388-022-02332-8.
Feifei Sun 1,  Xinpei Wang 1,  Jing Hu 2,  Junmei Liu 3,  Xin Wang 1,  Wenqiao Jia 4,  Zeyuan Yu 1,  Lin Gao 1,  Baokai Dou 5,  Ru Zhao 1,  Tingting Feng 1,  Xueli Wang 6,  Wenbo Zhang 1,  Hui Liu 2,  Kaihua Liu 7,  Yang Shao 7,  Xuesen Dong 8 9,  Bo Han 10 11
Affiliations

Affiliations

  • 1 The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, 250012, China.
  • 2 Department of Pathology, Qilu Hospital, Shandong University, Jinan, 250012, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jinan, 250012, China.
  • 4 Department of Health Management Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
  • 5 Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
  • 6 Department of Pathology, Binzhou City Central Hospital, Binzhou, China.
  • 7 Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China.
  • 8 Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, V6H 3Z6, Canada. [email protected].
  • 9 Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada. [email protected].
  • 10 The Key Laboratory of Experimental Teratology, Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, 250012, China. [email protected].
  • 11 Department of Pathology, Qilu Hospital, Shandong University, Jinan, 250012, China. [email protected].
PMID: 35508542 DOI: 10.1038/s41388-022-02332-8
Abstract

Although enzalutamide improves the overall survival of patients with metastatic prostate cancers, enzalutamide resistance (ENZR) will be inevitably developed. Emerging evidence support that alternative oncogenic pathways may bypass the Androgen Receptor (AR) signaling to promote ENZR progression, however, the underpinning mechanisms remain poorly defined. Here, we report that the expression of RuvB like AAA ATPase 1 (RUVBL1) is upregulated in ENZR cells and xenograft models and prostate tumors in patients. Enzalutamide increases RUVBL1 accumulation in the cytoplasm, which in turn enhances the recruitment of CRAF proto-oncogene serine/threonine kinase protein to plexin A1 (PLXNA1) and the subsequent activation of the downstream MAPK pathway. Co-overexpression of RUVBL1 and PLXNA1 defines a subgroup of prostate Cancer (PCa) patients with a poor prognosis. Furthermore, pharmacological inhibition of RUVBL1 by CB-6644 suppresses ENZR cell proliferation and xenograft growth and allows re-sensitization of ENZR cells and xenografts to enzalutamide, indicating that RUVBL1 may act to substitute the AR signaling to promote Cancer cell survival and ENZR development. Together, these findings may lead to the identification of RUVBL1 as a potential therapeutic target for ENZR tumors.

Figures
Products