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

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 24; pp. 11792 - 11801
• Main Authors: GAVRIELIDES, M. Veronica, GONZALEZ-GUERRICO, Anatilde M, RIOBO, Natalia A, KAZANIETZ, Marcelo G
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.12.2006
• Subjects: Antineoplastic agents; Biological and medical sciences; Gynecology. Andrology. Obstetrics; Male genital diseases; Medical sciences; Nephrology. Urinary tract diseases; Pharmacology. Drug treatments; Tumors; Tumors of the urinary system; Urinary tract. Prostate gland; Protein kinase C; Urinary system disease; Prostate disease; Androgen; Transcription; Enzyme; Transferases; Malignant tumor; Protein kinase Cδ; Sex steroid hormone; Male genital diseases; Prostate cancer; Tumor cell; Apoptosis
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-06-1139

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