Androgen receptor mediates non-genomic activation of phosphatidylinositol 3-OH kinase in androgen-sensitive epithelial cells.
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 Ser(473) and Thr(308) 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 p85alpha 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.
Baron
Silvère
S
Génétique des Eucaryotes et Endocrinologie Moléculaire, UMR 6547 CNRS-Université Blaise Pascal, Campus universitaire des Cézeaux, 24 Avenue des Landais, 63177 Aubière Cedex, France.
Manin
Michèle
M
Beaudoin
Claude
C
Leotoing
Laurent
L
Communal
Yves
Y
Veyssiere
Georges
G
Morel
Laurent
L
D000813:Anilides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology* / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008024:Ligands; D051379:Mice; D008957:Models, Genetic; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen / Q000502:physiology*; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013912:Threonine / Q000737:chemistry; D013997:Time Factors; D014105:Tosyl Compounds; D014158:Transcription, Genetic; D014162:Transfection; D051025:bcl-Associated Death Protein
D000813:Anilides; D002352:Carrier Proteins; D003513:Cycloheximide; D005982:Glutathione Transferase; D008024:Ligands; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011500:Protein Synthesis Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011944:Receptors, Androgen; D012694:Serine; D013912:Threonine; D014105:Tosyl Compounds; D051025:bcl-Associated Death Protein; C494819:BAD protein, human; C494820:Bad protein, mouse; C053541:bicalutamide; C494918:AKT1 protein, human