Tumor-promoting phorbol ester down-regulates the androgen induction of prostate-specific antigen in a human prostatic adenocarcinoma cell line.
Prostate-specific antigen (PSA) is the most sensitive marker available for monitoring the progression of prostate cancer and response to therapy. In a previous study, we demonstrated tissue-specific expression of PSA glycoprotein and mRNA and its regulation through the androgen receptor. In this study, we examine the effects of protein kinase A (PKA) and protein kinase C (PKC) on the androgen regulation of PSA in a human adenocarcinoma cell line, LNCaP. Northern blot analysis demonstrated that forskolin, an activator of PKA, had no effect on the androgen regulation of PSA. However, the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA), a direct activator of PKC, showed a time- and dose-dependent repression of the androgen regulation of PSA glycoprotein and mRNA. The biologically inactive phorbol ester, 4 alpha-phorbol-12,13-didecanoate, had no effect. Staurosporine, a PKC inhibitor, blocked the TPA-mediated repression of the androgenic stimulation of PSA glycoprotein. In addition, the calcium ionophore, A23187, was able to simulate the actions of TPA, presumably through activation of PKC via calcium mobilization. In summary, the androgenic regulation of PSA protein and mRNA is repressed by tumor-promoting phorbol esters through the PKC pathway. This indicates that the effects of TPA may be secondary to repressed gene transcription or altered mRNA stability. In addition, this study emphasizes that the androgenic regulation of PSA is complex and may involve other extracellular transduction signals.
Department of Urology, Mayo Clinic/Foundation, Rochester, Minnesota 55905.
P E
PE
Andrews
C Y
CY
Young
B T
BT
Montgomery
D J
DJ
Tindall
D000470:Alkaloids / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006801:Humans; D008297:Male; D009277:Nandrolone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010704:Phorbols / Q000494:pharmacology; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D019311:Staurosporine; D045165:Testosterone Congeners / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000470:Alkaloids; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D010704:Phorbols; D012333:RNA, Messenger; D045165:Testosterone Congeners; D005576:Colforsin; D000001:Calcimycin; D009277:Nandrolone; C100075:mibolerone; D017430:Prostate-Specific Antigen; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; C033085:phorbol