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

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.

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Authors

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.

Corresponding author

Correspondence to Marcus V. Cronauer.

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This article does not contain any studies with human participants or animals performed by any of the authors.

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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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Keywords

  • BET inhibitor
  • BRD4
  • Androgen receptor
  • AR-V7