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Novel inhibition of AKR1C3 and androgen receptor axis by PTUPB synergizes enzalutamide treatment in advanced prostate cancer

Oncogene volume 42, pages 693–707 (2023)Cite this article

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Abstract

Castration-resistant prostate cancer (CRPC) is the main driving force of mortality in prostate cancer patients. Among the parameters contributing to the progression of CRPC and treatment failure, elevation of the steroidogenic enzyme AKR1C3 and androgen receptor variant 7 (AR-V7) are frequently reported. The AKR1C3/AR-V7 complex has been recognized as a major driver for drug resistance in advanced prostate cancer. Herein we report that the level of AKR1C3 is reciprocally regulated by the full-length androgen receptor (AR-FL) through binding to the distal enhancer region of the AKR1C3 gene. A novel function of PTUPB in AKR1C3 inhibition was discovered and PTUPB showed more effectiveness than indomethacin and celecoxib in suppressing AKR1C3 activity and CRPC cell growth. PTUPB synergizes with enzalutamide treatment in tumor suppression and gene signature regulation. Combination treatments with PTUPB and enzalutamide provide benefits by blocking AR/AR-V7 signaling, which inhibits the growth of castration relapsed VCaP xenograft tumors and patient-derived xenograft organoids. Targeting of the ARK1C3/AR/AR-V7 axis with PTUPB and enzalutamide may overcome drug resistance to AR signaling inhibitors in advanced prostate cancer.

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Fig. 1: AR negatively regulates AKR1C3 expression in CRPC.
Fig. 2: A novel AKR1C3 inhibitor-PTUPB suppresses the AKR1C3 activity and intracrine androgen synthesis.
Fig. 3: PTUPB synergizes with the enzalutamide treatment and degrades AR/AR-V7 in vitro.
Fig. 4: Synergism of the PTUPB and enzalutamide combination treatment reprograms gene signature regulation and suppresses AR/AR-V7 signaling pathways in resistant prostate cancer.
Fig. 5: PTUPB improves enzalutamide treatment in LuCaP35CR organoid and relapsed VCaP xenograft tumor models.
Fig. 6: PTUPB suppresses the growth of patient-derived xenograft tumor cells and organoids.

Data availability

The RNA sequence data in the present study have been deposited in Gene Expression Omnibus (GEO) with the accession number GSE216777. All data are available from the authors upon reasonable request.

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Acknowledgements

We sincerely thank Dr. Bo Chen in the Department of Urologic Surgery, Dr. Justin Siegel and Simon Kit Sang Chu in the Department of Chemistry at UC Davis for their assistance in our study.

Funding

This work was supported in part by grants from NIH/NCI R37CA249108 (Liu), R01CA251253 (Liu), Paul Calabresi Clinical Oncology K12 Program (5K12CA138464-09, Lara and Liu), NIH/NIEHS (RIVER Award) R35ES030443 (Hammock), NIH/NIEHS (Superfund Award) P42 ES004699 (Hammock), and UC Davis Comprehensive Cancer Center Support Grant (CCSG) awarded by the NCI (NCI P30CA093373). The maintenance and characterization of the LuCaP PDX models were supported by the Pacific Northwest Prostate Cancer SPORE (P50CA97186), the Department of Defense Prostate Cancer Biorepository Network (W81XWH-14-2-0183), and NCI P01-CA163227.

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Authors and Affiliations

  1. Department of Urologic Surgery, University of California Davis, Davis, CA, USA

    Joy C. Yang, Pengfei Xu, Shu Ning, Logan J. Wasielewski, Allen C. Gao, Christopher P. Evans & Chengfei Liu

  2. Vancouver Prostate Centre, Vancouver, BC, Canada

    Hans Adomat & Martin Gleave

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

    Hans Adomat & Martin Gleave

  4. Department of Entomology and Nematology, University of California Davis, Davis, CA, USA

    Sung Hee Hwang, Christophe Morisseau & Bruce D. Hammock

  5. Department of Urology, University of Washington, Washington, WA, USA

    Eva Corey

  6. UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, USA

    Allen C. Gao, Primo N. Lara Jr, Christopher P. Evans, Bruce D. Hammock & Chengfei Liu

  7. Department of Internal Medicine, University of California Davis, Davis, CA, USA

    Primo N. Lara Jr

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  1. Joy C. Yang
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Contributions

JCY, BDH and CL conceived the project and designed the experiments. JCY, PX, HA, MG, and CL developed the methodology. JCY, PX, LJW, SN, and HA performed the experiments and acquired the data. MG, CPE, EC, ACG, PL, SHH, CM, and BDH provided technical and material support. SN and CL performed the bioinformatics analysis. JCY, CPE, SHH, BDH, and CL interpreted and analyzed the data. JCY and CL wrote the manuscript. LJW, SHH, CPE, and BDH edited the manuscript. CL supervised the study.

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Correspondence to Chengfei Liu.

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PTUPB is covered under a University of California Patent with SHH and BDH. Other authors declare no conflict of interest, financial or otherwise.

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Yang, J.C., Xu, P., Ning, S. et al. Novel inhibition of AKR1C3 and androgen receptor axis by PTUPB synergizes enzalutamide treatment in advanced prostate cancer. Oncogene 42, 693–707 (2023). https://doi.org/10.1038/s41388-022-02566-6

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