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

Marie C. Hupe, M. Raschid Hoda, Friedemann Zengerling, Sven Perner, Axel S. Merseburger, Marcus V. Cronauer*

*Korrespondierende/r Autor/-in für diese Arbeit

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.

OriginalspracheEnglisch
ZeitschriftWorld Journal of Urology
Jahrgang37
Ausgabenummer2
Seiten (von - bis)343-349
Seitenumfang7
ISSN0724-4983
DOIs
PublikationsstatusVeröffentlicht - 12.02.2019

Strategische Forschungsbereiche und Zentren

  • Profilbereich: Lübeck Integrated Oncology Network (LION)

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