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World J Urol. 2019 Feb;37(2):343-349. doi: 10.1007/s00345-018-2382-8. Epub 2018 Jun 22.

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

Author information

1
Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
2
Department of Urology, University of Ulm, 89075, Ulm, Germany.
3
Pathology of the University Hospital Schleswig-Holstein, Campus Lübeck and Research Center Borstel, Leibniz Center for Medicine and Biosciences, Borstel, Germany.
4
Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany. marcus.cronauer@uksh.de.

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.

KEYWORDS:

AR-V7; Androgen receptor; BET inhibitor; BRD4

PMID:
29934670
DOI:
10.1007/s00345-018-2382-8

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