Prostate cancer (PCa) remains a leading cause of
cancer-related death in men. Especially, a subset of patients will eventually progress to the metastatic castrate-resistant
prostate cancer (CRPC) which is currently incurable.
Deubiquitinases (DUBs) associated with the 19S
proteasome regulatory particle are increasingly emerging as significant therapeutic targets in numerous
cancers. Recently, a novel small molecule b-AP15 is identified as an inhibitor of the USP14/UCHL5 (DUBs) of the 19S
proteasome, resulting in cell growth inhibition and apoptosis in several human
cancer cell lines. Here, we studied the
therapeutic effect of b-AP15 in PCa, and our results indicate that (i) b-AP15 decreases viability, proliferation and triggers cytotoxicity to both
androgen receptor-dependent and -independent PCa cells in vitro and in vivo, associated with
caspase activation, inhibition of mitochondria function, increased
reactive oxygen species (ROS) generation and endoplasmic reticulum (ER) stress; (ii) pan-
caspase inhibitor
z-VAD-FMK and ROS scavenger
N-acetyl-L-cysteine (NAC) efficiently block apoptosis but not
proteasome inhibition induced by exposure of b-AP15; (iii) treatment with b-AP15 in
androgen-dependent
prostate cancer (ADPC) cells down-regulates the expression of
androgen receptor (AR), which is degraded via the
ubiquitin proteasome system. Hence, the potent anti-
tumor effect of b-AP15 on both
androgen receptor-dependent and -independent PCa cells identifies a new promising therapeutic strategy for
prostate cancer.