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Androgens Regulate Protein Kinase C Transcription and Modulate Its Apoptotic Function in Prostate Cancer Cells

Departments of ¹ Pharmacology and ² Emergency Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Requests for reprints: Marcelo G. Kazanietz, Department of Pharmacology, University of Pennsylvania School of Medicine, 816 Biomedical Research Building II/III, 421 Curie Boulevard, Philadelphia, PA 19104-6160. Phone: 215-898-0253; Fax: 215-573-9004; E-mail: marcelo{at}spirit.gcrc.upenn.edu.

Activation of protein kinase C (PKC), a member of the novel PKC family, leads to apoptosis in several cell types. Although the molecular bases of PKC activation are being unfolded, limited information is available on the mechanisms that control its expression. Here, we report that in prostate cancer cells PKC is tightly regulated by androgens at the transcriptional level. Steroid depletion from the culture medium causes a pronounced down-regulation of PKC 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 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 AR-binding consensus abolish reporter activity. Furthermore, using chromatin immunoprecipitation assays, we determined that the AR binds in vivo to the PKC 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. Indeed, androgen depletion or AR RNA interference severely impaired the apoptotic function of PKC or the activation of p38, a downstream effector of PKC in LNCaP cells—effects that can be rescued by restoring PKC levels using an adenoviral delivery approach. Our studies identified a novel hormonal mechanism for the control of PKC expression via transcriptional regulation that fine-tunes the magnitude of PKC apoptotic responses. (Cancer Res 2006; 66(24): 11792-801)

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