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

Oncogene volume 41, pages 3239–3250 (2022)Cite this article

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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.

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Fig. 1: Identification of RUVBL1 high expression in enzalutamide resistant CRPC.
Fig. 2: RUVBL1 promotes cell growth and xenograft progression.
Fig. 3: Enzalutamide can promote RUVBL1 cytoplasmic distribution.
Fig. 4: RUVBL1 activates MAPK signaling to promote the enzalutamide resistance.
Fig. 5: RUVBL1 activates MAPK pathway through the recruitment of PLXNA1 and CRAF.
Fig. 6: CB-6644 inhibits growth of enzalutamide resistant PCa in vitro and in vivo.

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Funding

This work was supported by the Joint Research Fund of Natural Science, Shandong Province (ZR2019LZL014), National Natural Science Foundation of China (Grant No. 81972416, 82172818), Major Science and Technology Innovation Project of Shandong Province (2018CXGC1210), the National Key Research and Development Program of China (2018YFC0114703), and The Fundamental Research Funds of Shandong University (2018JC016).

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Authors and 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

    Feifei Sun, Xinpei Wang, Xin Wang, Zeyuan Yu, Lin Gao, Ru Zhao, Tingting Feng, Wenbo Zhang & Bo Han

  2. Department of Pathology, Qilu Hospital, Shandong University, Jinan, 250012, China

    Jing Hu, Hui Liu & Bo Han

  3. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Jinan, 250012, China

    Junmei Liu

  4. Department of Health Management Center, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China

    Wenqiao Jia

  5. Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China

    Baokai Dou

  6. Department of Pathology, Binzhou City Central Hospital, Binzhou, China

    Xueli Wang

  7. Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China

    Kaihua Liu & Yang Shao

  8. Vancouver Prostate Centre, Vancouver General Hospital, Vancouver, BC, V6H 3Z6, Canada

    Xuesen Dong

  9. Department of Urologic Sciences, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada

    Xuesen Dong

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Contributions

Study concept and design: FS, XD, and BH. Data acquisition: FS, XW, TF, LG, WZ, XW, ZY, BD, and XW. Analysis and interpretation of the data: FS, XW, JL, WJ, Hl, KL, YS. Paper preparation: FS, BH, and XD. Critical review: BH, FS, XW, and XD.

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Correspondence to Xuesen Dong or Bo Han.

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Sun, F., Wang, X., Hu, J. et al. RUVBL1 promotes enzalutamide resistance of prostate tumors through the PLXNA1-CRAF-MAPK pathway. Oncogene 41, 3239–3250 (2022). https://doi.org/10.1038/s41388-022-02332-8

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