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

Momoe Itsumi, Masaki Shiota, Akira Yokomizo, Ario Takeuchi, Eiji Kashiwagi, Takashi Dejima, Junichi Inokuchi, Katsunori Tatsugami, Takeshi Uchiumi, Seiji Naito

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)31-41
Number of pages11
JournalJournal of Molecular Endocrinology
Volume53
Issue number1
DOIs
Publication statusPublished - Apr 29 2014

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Androgen Receptors
Prostatic Neoplasms
Acetates
Down-Regulation
Apoptosis
Androgens
Castration
phorbol-12-myristate
Therapeutic Uses
MDV 3100

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

Cite this

PMA induces androgen receptor downregulation and cellular apoptosis in prostate cancer cells. / Itsumi, Momoe; Shiota, Masaki; Yokomizo, Akira; Takeuchi, Ario; Kashiwagi, Eiji; Dejima, Takashi; Inokuchi, Junichi; Tatsugami, Katsunori; Uchiumi, Takeshi; Naito, Seiji.

In: Journal of Molecular Endocrinology, Vol. 53, No. 1, 29.04.2014, p. 31-41.

Research output: Contribution to journalArticle

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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.",
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