Androgen Receptor Mediates Non-genomic Activation of Phosphatidylinositol 3-OH Kinase in Androgen-sensitive Epithelial Cells

• Published in: The Journal of biological chemistry Vol. 279; no. 15; pp. 14579 - 14586
• Main Authors: Baron, Silvère, Manin, Michèle, Beaudoin, Claude, Leotoing, Laurent, Communal, Yves, Veyssiere, Georges, Morel, Laurent
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09-04-2004; American Society for Biochemistry and Molecular Biology
• Subjects: Anilides - pharmacology; Animals; Apoptosis; bcl-Associated Death Protein; Blotting, Western; Carrier Proteins - metabolism; Cell Line, Tumor; Cell Survival; Cycloheximide - pharmacology; Dose-Response Relationship, Drug; Enzyme Activation; Epithelial Cells - enzymology; Epithelial Cells - metabolism; Escherichia coli - metabolism; Glutathione Transferase - metabolism; Humans; Ligands; Mice; Models, Genetic; Nitriles; Phosphatidylinositol 3-Kinases - metabolism; Phosphorylation; Plasmids - metabolism; Protein Structure, Tertiary; Protein Synthesis Inhibitors - pharmacology; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Receptors, Androgen - physiology; Serine - chemistry; Signal Transduction; Threonine - chemistry; Time Factors; Tosyl Compounds; Transcription, Genetic; Transfection
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M306143200

Androgens are known to modulate many cellular processes such as cell growth and survival by binding to the androgen receptor (AR) and activating the transcription of target genes. Recent data suggested that AR can also mediate non-transcriptional actions outside the nucleus in addition to its ligand-inducible transcription factor function. Here, we describe a transcription-independent activation of the phosphatidylinositol 3-OH kinase (PI3-K) signaling pathway by androgens. Using non-transformed androgen-sensitive epithelial cells, we show that androgens enhance the PI3-K activity by promoting accumulation of phosphoinositide-3-P phospholipids in vitro. This activation is found in conjunction with an increased time-dependent phosphorylation of the downstream kinase AKT/protein kinase B on both Ser473 and Thr308 residues. Hormone-stimulated phosphorylation of AKT requires AR since incubation with the anti-androgen bicalutamide completely abolishes the androgen-stimulated AKT phosphorylation. Accordingly, we show that androgens increase AKT phosphorylation level in prostatic carcinoma PC3 cells only once they have been transfected with AR. Downstream, androgens enhance phosphorylation of transcription factor FKHR (Forkhead in rhabdomyosarcoma)-L1 and proapoptotic Bad protein and promote cell survival as they can counteract an apoptotic process. We also report that non-genomic effects of androgens are based on direct interaction between AR and the p85α regulatory subunit of class I(A) PI3-K. Together, these novel findings point out an important and physiologically relevant link between androgens and the PI3-K/AKT signaling pathway in governing cell survival.