title: Inhibition of apoptosis in prostate cancer cells by androgens is mediated through downregulation of c-Jun N-terminal kinase activation.
abstract: Androgen deprivation induces the regression of prostate tumors mainly due to an increase in the apoptosis rate; however, the molecular mechanisms underlying the antiapoptotic actions of androgens are not completely understood. We have studied the antiapoptotic effects of androgens in prostate cancer cells exposed to different proapoptotic stimuli. Terminal deoxynucleotidyl transferase-mediated nick-end labeling and nuclear fragmentation analyses demonstrated that androgens protect LNCaP prostate cancer cells from apoptosis induced by thapsigargin, the phorbol ester 12-O-tetradecanoyl-13-phorbol-acetate, or UV irradiation. These three stimuli require the activation of the c-Jun N-terminal kinase (JNK) pathway to induce apoptosis and in all three cases, androgen treatment blocks JNK activation. Interestingly, okadaic acid, a phosphatase inhibitor that causes apoptosis in LNCaP cells, induces JNK activation that is also inhibited by androgens. Actinomycin D, the antiandrogen bicalutamide or specific androgen receptor (AR) knockdown by small interfering RNA all blocked the inhibition of JNK activation mediated by androgens indicating that this activity requires AR-dependent transcriptional activation. These data suggest that the crosstalk between AR and JNK pathways may have important implications in prostate cancer progression and may provide targets for the development of new therapies.
authors.affiliation: Department of Molecular Biosciences, University of Oslo, Postboks 1041, Blindern, 0316 Oslo, Norway.
authors.forename: Petra Isabel
authors.initials: PI
authors.lastname: Lorenzo
authors.forename: Fahri
authors.initials: F
authors.lastname: Saatcioglu
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology; D059002:Androgen Receptor Antagonists; D000728:Androgens / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D009376:Neoplasms, Hormone-Dependent / Q000201:enzymology / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000473:pathology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
chemical_list: C410798:AR protein, human; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000728:Androgens; D000813:Anilides; D009570:Nitriles; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D019284:Thapsigargin; C053541:bicalutamide; D048031:JNK Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate