TUMOR-PROMOTING PHORBOL ESTER-INDUCED CELL-DEATH AND GENE-EXPRESSION IN A HUMAN PROSTATE ADENOCARCINOMA CELL-LINE

12-O-tetradecanoyl phorbol ester (TPA) has profound cytotoxic effects on a human prostate cancer cell line, LNCaP. The TPA effect may be med iated via a protein kinase C (PKC) pathway, since staurosporine, a pot ent PKC inhibitor, could reverse the cell-killing effect. Our studies, based on cellular fragmentation, chromatin condensation, and nuclear fragmentation, suggest that the cell-killing effect is due to apoptosi s. Moreover, we also examined expression of early growth response gene s and androgen-induced genes in association with TPA-induced apoptosis . Northern blot analysis demonstrated that androgen induction of human glandular kallikrein-1 (hKLK2) mRNA was repressed by TPA in a concent ration-dependent manner. A time course study showed that both hKLK2 an d c-myc mRNAs were repressed by TPA as early as four hours. In contras t, the steady state mRNA levels for c-fos, c-jun, nerve growth factor induced gene A, and the orphan steroid receptor nur77 were rapidly ind uced within the first two hours of the treatment. Furthermore, transie nt co-transfection experiments demonstrated that c-fos and c-jun could repress androgen receptor-mediated gene induction. The above studies suggest that (1) the repression of androgen induction of gene expressi on by TPA-activated PKC is at least in part due to overexpression of c -jun and c-fos and (2) PKC may be a negative growth regulator in prost ate cells.