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GRK2 enforces androgen receptor dependence in the prostate and prostate tumors

Oncogene volume 39, pages 2424–2436 (2020)Cite this article

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Abstract

Metastatic tumors that have become resistant to androgen deprivation therapy represent the major challenge in treating prostate cancer. Although these recurrent tumors typically remain dependent on the androgen receptor (AR), non-AR-driven tumors that also emerge are particularly deadly and becoming more prevalent. Here, we present a new genetically engineered mouse model for non-AR-driven prostate cancer that centers on a negative regulator of G protein-coupled receptors that is downregulated in aggressive human prostate tumors. Thus, prostate-specific expression of a dominant-negative G protein-coupled receptor kinase 2 (GRK2-DN) transgene diminishes AR and AR target gene expression in the prostate, and confers resistance to castration-induced involution. Further, the GRK2-DN transgene dramatically accelerates oncogene-initiated prostate tumorigenesis by increasing primary tumor size, potentiating visceral organ metastasis, suppressing AR, and inducing neuroendocrine marker mRNAs. In summary, GRK2 enforces AR-dependence in the prostate, and the loss of GRK2 function in prostate tumors accelerates disease progression toward the deadliest stage.

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Fig. 1: GRK2-DN transgenic mice.
Fig. 2: GRK2 blockade accelerates prostate tumorigenesis.
Fig. 3: Occurrence of metastasis (abbreviated as “Mets”) in TRAMP versus G2-TP mice.
Fig. 4: GRK2 blockade diminishes transgene and androgen receptor (AR) expression.
Fig. 5: GRK2 blockade suppresses androgen-responsive target gene expression in the prostate and prostate tumors.
Fig. 6: GRK2 blockade alters prostatic 5α-reductase expression.
Fig. 7: GRK2 blockade augments the expression of neuroendocrine marker mRNAs in prostate tumors.
Fig. 8: GRK2 blockade mitigates castration-induced prostate involution.

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Acknowledgements

This work was supported by National Institutes of Health Grants R01CA109339 and R01AI094640 (to AJA and ATV) and by the Carole and Ray Neag Comprehensive Cancer Center. The authors thank Dr. Jeffrey Benovic for providing the GRK2-DN (βARK-K220R) construct, Dr. Robert Matusik for providing the ARR2PB construct as well as helpful discussions and critical reading of the paper, Dr. Stefan Brocke for advice regarding in vitro forskolin stimulations, and Dr. Christopher Bonin for editing the paper.

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  1. Payal Mittal

    Present address: Merck Research Laboratories, Oncology Department, Boston, MA, 02115, USA

  2. Adam T. Hagymasi

    Present address: Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT, USA

Authors and Affiliations

  1. Department of Immunology, School of Medicine, UConn Health, Farmington, CT, USA

    Adam J. Adler, Payal Mittal, Adam T. Hagymasi, Antoine Menoret, Chen Shen, Federica Agliano, Kyle T. Wright & Anthony T. Vella

  2. Department of Community Medicine and Health Care, School of Medicine, UConn Health, Farmington, CT, USA

    James J. Grady & Chia-Ling Kuo

  3. Department of Pathology and Laboratory Medicine, School of Medicine, UConn Health, Farmington, CT, USA

    Enrique Ballesteros

  4. Department of Cell Biology, School of Medicine, UConn Health, Farmington, CT, USA

    Kevin P. Claffey

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Adler, A.J., Mittal, P., Hagymasi, A.T. et al. GRK2 enforces androgen receptor dependence in the prostate and prostate tumors. Oncogene 39, 2424–2436 (2020). https://doi.org/10.1038/s41388-020-1159-x

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