PMA induces androgen receptor downregulation and cellular apoptosis in prostate cancer cells.
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 castration-resistant cells. Taken together, PMA derivatives may be promising therapeutic agents for treating prostate cancer patients including CRPC patients.
Departments of UrologyClinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Momoe
M
Itsumi
Departments of UrologyClinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Masaki
M
Shiota
Departments of UrologyClinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan yokoa@uro.med.kyushu-u.ac.jp.
Akira
A
Yokomizo
Departments of UrologyClinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Ario
A
Takeuchi
Departments of UrologyClinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Eiji
E
Kashiwagi
Departments of UrologyClinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Takashi
T
Dejima
Departments of UrologyClinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Junichi
J
Inokuchi
Departments of UrologyClinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Katsunori
K
Tatsugami
Departments of UrologyClinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Takeshi
T
Uchiumi
Departments of UrologyClinical Chemistry and Laboratory MedicineGraduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Seiji
S
Naito
D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D001549:Benzamides; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009570:Nitriles; D011944:Receptors, Androgen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D010669:Phenylthiohydantoin; C540278:enzalutamide; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate
E2F1; androgen receptor; phorbol 12-myristate 13-acetate; prostate cancer