Phorbol ester-induced apoptosis is accompanied by NGFI-A and c-fos activation in androgen-sensitive prostate cancer cells.

We have previously demonstrated the induction of the early response transcription factor NGFI-A in castration-induced regression of the rat ventral prostate. We have developed an in vitro model to investigate the role of kinase signal transduction and early transcriptional regulation in apoptosis of androgen-sensitive prostate cells. Cell death was induced in the androgen-sensitive human prostate line, LNCaP, by addition of the protein kinase activator, 12-tetradecanoylphorbol 13-acetate (TPA). TPA-induced death of LNCaP cells was asynchronous and exhibited morphological and ultrastructural features indicative of apoptosis. Specifically, cytoplasmic contraction, condensation of nuclear chromatin, and formation of membrane-bound "apoptotic bodies" were observed. Additionally, the characteristic endonuclease-generated DNA ladder, commonly associated with apoptosis, was observed in TPA-treated LNCaP cultures. TPA-induced LNCaP apoptosis was preceded by rapid yet transient induction of the early response transcription factors NGFI-A and c-fos. In dose-response experiments, NGFI-A and c-fos gene activation parallels the induction of death in LNCaP cells. TPA-induced expression of NGFI-A and c-fos and death of LNCaP cultures were blocked by pretreatment with staurosporine, a potent inhibitor of several protein kinases. Based on these studies, we suggest that activation of a TPA-inducible kinase(s) mediates apoptosis of androgen-sensitive prostate cells by means of an intracellular pathway that may involve the transient activation of the early response transcription factors NGFI-A and c-fos.