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Androgen receptor phosphorylation at serine 81 and serine 213 in castrate-resistant prostate cancer

Prostate Cancer and Prostatic Diseases volume 23, pages 596–606 (2020)Cite this article

Subjects

Abstract

Background

Despite increases in diagnostics and effective treatments, over 300,000 men die from prostate cancer highlighting the need for specific and differentiating biomarkers. AR phosphorylation associates with castrate-resistance, with pARser213 promoting transcriptional activity. We hypothesise that combined pARser81 and pARser213 reduces survival and would benefit from dual-targeting androgen-dependent and Akt-driven disease.

Methods

Immunohistochemistry and immunofluorescence were performed on matched hormone-naive and castrate-resistant prostate cancer samples. TempO-Seq gene profiling was analysed using DESeq2 package. LNCaP-AI cells were stimulated with DHT or EGF. WST-1 assays were performed to determine effects of Enzalutamide and BKM120 on cell viability.

Results

Following the development of castrate-resistance, pARser81 expression reduced and pARser213 expression increased. Castrate-resistance pARser81 expression was not associated with survival but high pARser213 expression was associated with reduced survival from relapse. Combined high pARser81 and pARser213 was associated with reduced survival from relapse. pARser81 expression was induced by 10 nM DHT or 10 nM EGF and pARser213 expression was induced by treatment with 10 nM EGF in LNCaP-AI cells. Cell viability was reduced following treatment with 10 nM Enzalutamide and 10 nM BKM120. Eight genes were differentially expressed between hormone-naive and castrate-resistant tumours and twenty-five genes were differentially expressed between castrate-resistant tumours with high and low pARser213 expression.

Conclusion

Combined pARser81 and pARser213 provides a novel prognostic biomarker for castrate-resistant disease and a potential predictive and therapeutic target for prostate cancer. Further studies will be required to investigate the combined effects of targeting AR and PI3K/AKT signalling.

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Fig. 1: Androgen receptor phosphorylation status between hormone-naive and castrate-resistant prostate cancer.
Fig. 2: Combined pARser81 and pARser213 expression in castrate-resistant tumours.
Fig. 3: Stimulating androgen-dependent androgen receptor signalling in LNCaP-AI cells.
Fig. 4: Stimulating androgen-independent androgen receptor signalling in LNCaP-AI cells.
Fig. 5: Inhibiting androgen receptor signalling in LNCaP-AI cells.

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Acknowledgements

We thank Prostate Cancer UK (S14-003) for funding the research presented. We would like to acknowledge the Glasgow Research Tissue Facility and Glasgow Biorepository for supporting this study.

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Authors and Affiliations

  1. Unit of Gastrointestinal Cancer and Molecular Pathology, Institute of Cancer Sciences, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, G61 1QH, UK

    Milly J. McAllister, Pamela McCall, Ashley Dickson, Hing Y. Leung & Joanne Edwards

  2. Department of Urology, Queen Elizabeth University Hospital, Glasgow, G31 2ER, UK

    Mark A. Underwood & Hing Y. Leung

  3. BioClavis Ltd, Glasgow, G51 4TF, UK

    Ditte Andersen & Elizabeth Holmes

  4. Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK

    Elke Markert & Hing Y. Leung

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Correspondence to Milly J. McAllister.

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McAllister, M.J., McCall, P., Dickson, A. et al. Androgen receptor phosphorylation at serine 81 and serine 213 in castrate-resistant prostate cancer. Prostate Cancer Prostatic Dis 23, 596–606 (2020). https://doi.org/10.1038/s41391-020-0235-1

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