Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells.
The androgen receptor (AR) can be activated in the absence of androgens by interleukin-6 (IL-6) in human prostate cancer cells. The events involved in ligand-independent activation of the AR are unknown, but have been suggested to involve phosphorylation of the AR itself or a receptor-associated protein. Steroid receptor coactivator-1 (SRC-1) has been shown to interact with the human AR and to modulate ligand-dependent AR transactivation and is regulated by phosphorylation by MAPK. To date, no one has examined the role of SRC-1 in ligand-independent activation of the AR by IL-6 or other signaling pathways known to activate the full-length receptor. This study addressed this and has revealed the following. 1) SRC-1 similarly enhanced ligand-independent activation of the AR by IL-6 to the same magnitude as that obtained via ligand-dependent activation. 2) Androgen and IL-6 stimulated the MAPK pathway. 3) MAPK was required for both ligand-dependent and ligand-independent activation of the AR. 4) Phosphorylation of SRC-1 by MAPK was required for optimal ligand-independent activation of the AR by IL-6. 5) Protein-protein interaction between endogenous AR and SRC-1 was dependent upon treatment of LNCaP cells with IL-6 or R1881. 6) Protein-protein interaction between the AR N-terminal domain and SRC-1 was independent of MAPK. 7) Ligand-independent activation of the AR did not occur by a mechanism of overexpression of either solely wild-type SRC-1 or mutant SRC-1 that mimics its phosphorylated form.
Ueda
Takeshi
T
Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, British Columbia V5Z 4E6, Canada.
Mawji
Nasrin R
NR
Bruchovsky
Nicholas
N
Sadar
Marianne D
MD
D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D015741:Metribolone / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D056920:Nuclear Receptor Coactivator 1; D011471:Prostatic Neoplasms / Q000378:metabolism*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D045165:Testosterone Congeners / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D015850:Interleukin-6; D008024:Ligands; D011944:Receptors, Androgen; D045165:Testosterone Congeners; D015534:Trans-Activators; D014157:Transcription Factors; D015741:Metribolone; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1; D020928:Mitogen-Activated Protein Kinases