title: A Signaling Network Controlling Androgenic Repression of c-Fos Protein in Prostate Adenocarcinoma Cells.
abstract: The transcription factor c-Fos controls many important cellular processes, including cell growth and apoptosis. c-Fos expression is rapidly elevated in the prostate upon castration-mediated androgen withdrawal through an undefined mechanism. Here we show that androgens (5α-dihydrotestosterone and R1881) suppress c-Fos protein and mRNA expression induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) or EGF in human prostate cancer (PCa) cell lines. Such suppression transpires through a transcriptional mechanism, predominantly at the proximal serum response element of the c-fos promoter. We show that androgen signaling suppresses TPA-induced c-Fos expression through repressing a PKC/MEK/ERK/ELK-1 signaling pathway. Moreover, our results support the hypothesis that p38(MAPK), PI3K, and PKCδ are involved in the androgenic regulation of c-Fos through controlling MEK/ERK. Stable silencing of c-Fos and PKCδ with shRNAs suggests that R1881 promotes cell death induced by low-dose TPA through a mechanism that is dependent on both PKCδ and loss of c-Fos expression. Reciprocally, loss of either PKCδ or c-Fos activates p38(MAPK) while suppressing the activation of ERK1/2. We also provide the first demonstration that R1881 permits cell death induced by low-dose TPA in the LNCaP androgen-dependent PCa cell line and that TPA-induced cell death is independent of exogenous androgen in the castration-resistant variants of LNCaP, C4-2 and C4-2B. Acquisition of androgen-independent killing by TPA correlates with activation of p38(MAPK), suppression of ERK1/2, and loss of c-Fos. These results provide new insights into androgenic control of c-Fos and use of PKC inhibitors in PCa therapy.
authors.affiliation: Division of General Medical Sciences-Oncology.
authors.forename: Eswar
authors.initials: E
authors.lastname: Shankar
authors.affiliation: Division of General Medical Sciences-Oncology.
authors.forename: Kyung
authors.initials: K
authors.lastname: Song
authors.affiliation: Division of General Medical Sciences-Oncology.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Corum
authors.affiliation: Division of General Medical Sciences-Oncology.
authors.forename: Kara L
authors.initials: KL
authors.lastname: Bane
authors.affiliation: Department of Pharmacology, and.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106 and; From the Case Comprehensive Cancer Center.
authors.forename: Hung-Ying
authors.initials: HY
authors.lastname: Kao
authors.affiliation: Division of General Medical Sciences-Oncology,; Department of Pharmacology, and; the Department of Urology, University Hospitals of Cleveland, Cleveland, Ohio 44106; From the Case Comprehensive Cancer Center,. Electronic address: dxd49@case.edu.
authors.forename: David
authors.initials: D
authors.lastname: Danielpour
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000728:Androgens / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D015741:Metribolone / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000728:Androgens; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D013196:Dihydrotestosterone; D015741:Metribolone; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate
keywords: Akt PKB; MAPK; PKC; androgen; androgen receptor; c-Fos; c-Jun transcription factor; p38 MAPK; phorbol ester; prostate cancer