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.

journal_name

World J Urol

journal_title

World journal of urology

authors

Hupe MC,Hoda MR,Zengerling F,Perner S,Merseburger AS,Cronauer MV

doi

10.1007/s00345-018-2382-8

subject

Has Abstract

pub_date

2019-02-01 00:00:00

pages

343-349

issue

2

eissn

0724-4983

issn

1433-8726

pii

10.1007/s00345-018-2382-8

journal_volume

37

pub_type

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