Androgens regulate protein kinase Cδ transcription and modulate its apoptotic function in prostate cancer cells

Activation of protein kinase C delta (PKC delta), a member of the novel PKC family, leads to apoptosis in several cell types. Although the molecular bases of PKC delta activation are being unfolded, limited information is available on the mechanisms that control its expression. Here, we report that in prostate cancer cells PKC delta is tightly regulated by androgens at the transcriptional level. Steroid depletion from the culture medium causes a pronounced down-regulation of PKC delta protein and mRNA in androgen-sensitive LNCaP prostate cancer cells, an effect that is rescued by the androgen R1881 in an androgen receptor (AR)-dependent manner. Analysis of the PKC delta promoter revealed a putative androgen responsive element (ARE) located 4.7 kb upstream from the transcription start site. Luciferase reporter assays show that this element is highly responsive to androgens, and mutations in key nucleotides in the All-binding consensus abolish reporter activity. Furthermore, using chromatin immunoprecipitation assays, we determined that the AR binds in vivo to the PKC delta ARE in response to androgen stimulation. Functional studies revealed that, notably, androgens modulate phorbol 12-myristate 13-acetate (PMA)-induced apoptosis in LNCaP cells, an effect that is dependent on PKC delta. Indeed, androgen depletion or AR RNA interference severely impaired the apoptotic function of PKC delta or the activation of p38, a downstream effector of PKC delta in LNCaP cells-effects that can be rescued by restoring PKC delta levels using an adenoviral delivery approach. Our studies identified a novel hormonal mechanism for the control of PKC delta expression via transcriptional regulation that fine-tunes the magnitude of PKC delta apoptotic responses.