Androgen deprivation
therapy in
prostate cancer is extremely effective; however, due to the continuous expression and/or mutagenesis of
androgen receptor (AR), the resistance to antihormonal
therapy is a natural progression. Consequently, targeting the AR for degradation offers an alternate approach to overcome this resistance in
prostate cancer. In this study, we demonstrate that
carnosic acid, a benzenediol
diterpene, binds the
ligand-binding domain of the AR and degrades the AR via endoplasmic reticulum (ER) stress-mediated proteasomal degradative pathway. In vitro,
carnosic acid treatment induced degradation of AR and decreased expression of
prostate-specific antigen in human
prostate cancer cell lines LNCaP and 22Rv1.
Carnosic acid also promoted the expression of ER
proteins including BiP and CHOP in a dose-dependent manner. Downregulation of CHOP by
small interfering RNA somewhat restored expression of AR suggesting that AR degradation is dependent on ER stress pathway. Future studies will need to evaluate other aspects of the unfolded protein response pathway to characterize the regulation of AR degradation. Furthermore, cotreating cells individually with
carnosic acid and
proteasome inhibitor (MG-132) and
carnosic acid and an ER stress modulator (
salubrinal) restored
protein levels of AR, suggesting that AR degradation is mediated by ER stress-dependent proteasomal degradation pathway. Degradation of AR and induction of CHOP
protein were also evident in vivo along with a 53% reduction in growth of xenograft
prostate cancer tumors. In addition,
carnosic acid-induced ER stress in
prostate cancer cells but not in normal prostate epithelial cells procured from patient biopsies. In conclusion, these data suggest that molecules such as
carnosic acid could be further evaluated and optimized as a potential therapeutic alternative to target AR in
prostate cancer.