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Dihydrotestosterone promotes kidney cancer cell proliferation by activating the STAT5 pathway via androgen and glucocorticoid receptors

  • Original Article – Cancer Research
  • Published:
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Abstract

Purpose

Androgen receptors (ARs) are expressed on a variety of cell types, and AR signaling plays an important role in tumor development and progression in several cancers. This in vitro study evaluated the effect of dihydrotestosterone (DHT) on the proliferation of renal cell carcinoma (RCC) cells in relation to AR status.

Methods

Steroid hormone receptor expression was evaluated using RT-PCR and Western blotting. The effect of DHT on cell proliferation and STAT5 phosphorylation was evaluated in RCC cell lines (Caki-2, A498, and SN12C) and primary RCC cells using cell viability assays and Western blotting. ARs and glucocorticoid receptors (GRs) were knocked down with small interfering RNAs before assessing changes in cell proliferation and STAT5 activation.

Results

DHT treatment promoted cell proliferation and increased STAT5 phosphorylation regardless of AR status. The AR antagonist bicalutamide reduced kidney cancer cell proliferation, regardless of AR status. AR and GR knockdown blocked STAT5 activation and reduced cell proliferation in all RCC cell lines. In patient-derived primary cells, DHT enhanced cell proliferation and this effect was diminished by treatment with the AR antagonists bicalutamide and enzalutamide and the GR antagonist mifepristone.

Conclusion

DHT promotes cell proliferation through STAT5 activation in RCC cells, regardless of AR status. DHT appears to utilize the AR and GR pathways to activate STAT5, and the inhibition of AR and GR showed antitumor activity in RCC cells. These data suggest that targeting AR and GR may be a promising new approach to the treatment of RCC.

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Acknowledgements

This study was supported by a Grant (W2014-012) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.

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Author notes

  1. Sahyun Pak and Wansuk Kim contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Center for Urologic Cancer, National Cancer Center, Goyang, Korea

    Sahyun Pak

  2. Department of Urology, Inje University Busan Paik Hospital, Busan, Korea

    Wansuk Kim

  3. Asan Institute for Life Science, Asan Medical Center, Seoul, Korea

    Yunlim Kim

  4. Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea

    Yunlim Kim, Cheryn Song & Hanjong Ahn

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  1. Sahyun Pak
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  2. Wansuk Kim
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  5. Hanjong Ahn
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Correspondence to Hanjong Ahn.

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Pak, S., Kim, W., Kim, Y. et al. Dihydrotestosterone promotes kidney cancer cell proliferation by activating the STAT5 pathway via androgen and glucocorticoid receptors. J Cancer Res Clin Oncol 145, 2293–2301 (2019). https://doi.org/10.1007/s00432-019-02993-1

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  • DOI: https://doi.org/10.1007/s00432-019-02993-1

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