TY - JOUR
T1 - The BET-inhibitor PFI-1 diminishes AR/AR-V7 signaling in prostate cancer cells
AU - Hupe, Marie C.
AU - Hoda, M. Raschid
AU - Zengerling, Friedemann
AU - Perner, Sven
AU - Merseburger, Axel S.
AU - Cronauer, Marcus V.
PY - 2019/2/12
Y1 - 2019/2/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85048860335&partnerID=8YFLogxK
U2 - 10.1007/s00345-018-2382-8
DO - 10.1007/s00345-018-2382-8
M3 - Journal articles
C2 - 29934670
AN - SCOPUS:85048860335
SN - 0724-4983
VL - 37
SP - 343
EP - 349
JO - World Journal of Urology
JF - World Journal of Urology
IS - 2
ER -