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The BET-inhibitor PFI-1 diminishes AR/AR-V7 signaling in prostate cancer cells

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Abstract

Objective

The bromodomain and extra-terminal (BET) family of proteins provides a scaffolding platform for the recruitment and tethering of transcription factors to acetylated chromatin, thereby modulating gene expression. In this study, we evaluated the efficacy of the BET-inhibitor PFI-1 to diminish AR/AR-V7 signaling and proliferation in castration-resistant prostate cancer cells.

Methods

Prostate-specific antigen and androgen receptor (AR) protein were quantified by means of two commercial ELISAs. Transactivation of the AR, AR-V7 and Q641X was determined by reporter gene assays. Cell proliferation was measured using a colorimetric MTT-assay.

Results

PFI-1 dose-dependently inhibited transactivation of full-length AR (non- mutated, i.e., wild-type or point-mutated/promiscuous forms) without affecting their cellular protein levels. Moreover, PFI-1 was active against C-terminally truncated constitutively active ARs like AR-V7 and Q641X. Prostate cancer cells exhibiting a transcriptionally active AR-signaling complex (LNCaP, 22Rv1) were more susceptible to the growth-inhibitory effects than the AR-negative PC-3 cells.

Conclusion

The quinazolinone PFI-1 is a highly efficient inhibitor of AR-signaling-competent prostate cancer cells in vitro. PFI-1 could serve as a lead compound for the development of new therapeutics able to block AR/AR-V7 signaling in advanced prostate cancer.

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Acknowledgements

The authors wish to thank Beate Godau and Christine Marschke for expert technical assistance.

Author information

Author notes

  1. Marie C. Hupe and M. Raschid Hoda equally contributed to this paper.

Authors and Affiliations

  1. Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany

    Marie C. Hupe, M. Raschid Hoda, Axel S. Merseburger & Marcus V. Cronauer

  2. Department of Urology, University of Ulm, 89075, Ulm, Germany

    Friedemann Zengerling

  3. Pathology of the University Hospital Schleswig-Holstein, Campus Lübeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany

    Sven Perner

Authors
  1. Marie C. Hupe
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  2. M. Raschid Hoda
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  4. Sven Perner
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  5. Axel S. Merseburger
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  6. Marcus V. Cronauer
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Contributions

MCH: data collection and protocol development; MHR: data collection; FZ: data collection; SP: data analysis; ASM: data analysis and manuscript writing/editing; MVC: project development, data analysis, and manuscript writing.

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Correspondence to Marcus V. Cronauer.

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Hupe, M.C., Hoda, M.R., Zengerling, F. et al. The BET-inhibitor PFI-1 diminishes AR/AR-V7 signaling in prostate cancer cells. World J Urol 37, 343–349 (2019). https://doi.org/10.1007/s00345-018-2382-8

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  • DOI: https://doi.org/10.1007/s00345-018-2382-8

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