Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells

J Biol Chem. 2002 Oct 11;277(41):38087-94. doi: 10.1074/jbc.M203313200. Epub 2002 Aug 5.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Genes, Reporter
  • Histone Acetyltransferases
  • Humans
  • Interleukin-6 / metabolism*
  • Ligands
  • MAP Kinase Signaling System / physiology
  • Male
  • Metribolone / metabolism
  • Mitogen-Activated Protein Kinases / metabolism
  • Nuclear Receptor Coactivator 1
  • Prostatic Neoplasms / metabolism*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Testosterone Congeners / metabolism
  • Trans-Activators / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Tumor Cells, Cultured


  • Interleukin-6
  • Ligands
  • Receptors, Androgen
  • Testosterone Congeners
  • Trans-Activators
  • Transcription Factors
  • Metribolone
  • Histone Acetyltransferases
  • NCOA1 protein, human
  • Nuclear Receptor Coactivator 1
  • Mitogen-Activated Protein Kinases