PKC-mediated secretion of death factors in LNCaP prostate cancer cells is regulated by androgens

• Published in: Molecular carcinogenesis Vol. 48; no. 3; pp. 187 - 195
• Main Authors: Xiao, Liqing, Gonzalez-Guerrico, Anatilde, Kazanietz, Marcelo G.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.03.2009
• Subjects: androgens; apoptosis; Apoptosis - drug effects; Blotting, Western; Cell Line, Tumor; Culture Media, Conditioned - pharmacology; Enzyme-Linked Immunosorbent Assay; Humans; JNK; JNK Mitogen-Activated Protein Kinases - metabolism; Male; Metribolone - pharmacology; p38 MAPK; p38 Mitogen-Activated Protein Kinases - metabolism; PKC; PMA; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Kinase C-delta - antagonists & inhibitors; Protein Kinase C-delta - genetics; Protein Kinase C-delta - metabolism; Receptors, Androgen - genetics; Receptors, Androgen - metabolism; RNA, Neoplasm - genetics; RNA, Neoplasm - metabolism; RNA, Small Interfering - pharmacology; Signal Transduction; Tetradecanoylphorbol Acetate - pharmacology; TNF-Related Apoptosis-Inducing Ligand - genetics; TNF-Related Apoptosis-Inducing Ligand - metabolism; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.20476

Activation of PKCδ in androgen‐dependent LNCaP prostate cancer cells leads to apoptosis via the activation of p38 MAPK and JNK cascades. We have recently shown that treatment of LNCaP cells with phorbol 12‐myristate 13‐acetate (PMA) leads to a PKCδ‐mediated autocrine release of death factors, including the cytokines TNFα and TRAIL, and that conditioned medium (CM) collected from PMA‐treated LNCaP cells promotes the activation of the extrinsic apoptotic cascade. Interfering with this autocrine loop either at the level of factor release or death receptor activation/signaling markedly impaired the PMA apoptotic response. In the present study we show that this PKCδ‐dependent autocrine mechanism is greatly influenced by androgens. Indeed, upon androgen depletion, which down‐regulates PKCδ expression, TNFα and TRAIL mRNA induction and release by PMA are significantly diminished, resulting in a reduced apoptogenic activity of the CM and an impaired ability of the CM to activate p38 MAPK and JNK. These effects can be rescued by addition of the synthetic androgen R1881. Furthermore, RNAi depletion of the androgen‐receptor (AR) from LNCaP cells equally impaired PMA responses, suggesting that PKC‐mediated induction of death factor secretion and apoptosis in LNCaP prostate cancer cells are highly sensitive to hormonal control. © 2008 Wiley‐Liss, Inc.