PMA induces androgen receptor downregulation and cellular apoptosis in prostate cancer cells

Abstract

Phorbol 12-myristate 13-acetate (PMA) induces cellular apoptosis in prostate cancer cells, the growth of which is governed by androgen/androgen receptor (AR) signaling, but the mechanism by which PMA exerts this effect remains unknown. Therefore, in this study, we investigated the mechanistic action of PMA in prostate cancer cells with regard to AR. We showed that PMA decreased E2F1 as well as AR expression in androgen-dependent prostate cancer LNCaP cells. Furthermore, PMA activated JNK and p53 signaling, resulting in the induction of cellular apoptosis. In LNCaP cells, androgen deprivation and a novel anti-androgen enzalutamide (MDV3100) augmented cellular apoptosis induced by PMA. Moreover, castration-resistant prostate cancer (CRPC) C4-2 cells were more sensitive to PMA compared with LNCaP cells and were sensitized to PMA by enzalutamide. Finally, the expression of PKC, E2F1, and AR was diminished in PMA-resistant cells, indicating that the gain of independence from PKC, E2F1, and AR functions leads to PMA resistance. In conclusion, PMA exerted its anti-cancer effects via the activation of pro-apoptotic JNK/p53 and inhibition of pro-proliferative E2F1/AR in prostate cancer cells including CRPC cells. The therapeutic effects of PMA were augmented by androgen deletion and enzalutamide in androgen-dependent prostate cancer cells, as well as by enzalutamide in castrationresistant cells. Taken together, PMA derivatives may be promising therapeutic agents for treating prostate cancer patients including CRPC patients.

Equol inhibits prostate cancer growth through degradation of androgen receptor by S‐phase kinase‐associated protein 2

“…Cytotoxicity analysis was carried out as described previously . Briefly, prostate cancer cells (2 × 10 3 ) were seeded in 96‐well plates.…”

“…Whole‐cell extracts and Western blot analyses were prepared as described previously . Briefly, the concentration of the prepared protein extracts was quantified using a Protein Assay (Bio‐Rad) based on the Bradford method.…”

“…Whole-cell extracts and Western blot analyses were prepared as described previously. (17)(18)(19)(20) Briefly, the concentration of the prepared protein extracts was quantified using a Protein Assay (Bio-Rad) based on the Bradford method. Aliquots (20 lg protein) were separated by 4-20% SDS-PAGE and transferred to PVDF microporous membranes (GE Healthcare Bio-Sciences, Piscataway, NJ, USA) using a semi-dry blotter.…”

“…Cytotoxicity analysis was carried out as described previously. (18)(19)(20) Briefly, prostate cancer cells (2 9 10 3 ) were seeded in 96-well plates. On the following day, cells were cultured with FBS or charcoal-stripped serum (CSS)-supplemented media with or without 1 nM DHT for 24 h and various concentrations of equol were applied.…”

Transcriptional activation of PRMT5 by NF-Y is required for cell growth and negatively regulated by the PKC/c-Fos signaling in prostate cancer cells

“…Given that PMA-induced down-regulation of PRMT5 is mainly observed in AR positive LNCaP cells, but not in AR negative DU 145 and PC-3 cells, it is plausible to hypothesize that down-regulation of PRMT5 by PMA in LNCaP cells may contribute to the suppression of LNCaP cell growth and induction of apoptosis by attenuating the AR activity [61]. As a recent report shows that PMA treatment in LNCaP cells can down-regulate AR expression [62], it would be interesting to examine whether PRMT5 has any effect on AR expression. Alternatively, PMA-induced PRMT5 down-regulation may contribute to PMA-induced apoptosis by enhancing the activity of p38δ, a major serine/threonine protein kinase mediating PMA-induced apoptosis in LNCaP cells [26].…”