Androgen receptor (AR) signaling promotes RCC progression via increased endothelial cell proliferation and recruitment by modulating AKT → NF-κB → CXCL5 signaling

Sci Rep. 2016 Nov 16:6:37085. doi: 10.1038/srep37085.

Abstract

Androgen receptor (AR) signaling may promote renal cell carcinoma (RCC) progression via altered HIF-2α/VEGF signaling. However, it remains unclear whether AR signaling also promotes RCC progression by recruiting vascular endothelial cells (ECs), key players in the development of blood vessels. In our study, AR increased EC proliferation and recruitment to the tumor microenvironment and promoted RCC progression. Mechanistically, AR modulated cytokine CXCL5 expression by altering AKT → NF-κB signaling, and interruption of AKT → NF-κB → CXCL5 signaling using either specific inhibitors or siRNA suppressed AR-enhanced EC recruitment and AR-EC-promoted RCC progression. The results obtained using an in vivo mouse model and a human clinical sample survey confirmed the role of AR in promoting RCC progression through enhancement of EC proliferation and/or recruitment via altered AKT → NF-κB → CXCL5 signaling. Targeting this newly identified AR-induced AKT → NF-κB → CXCL5 pathway may facilitate the development of new therapies for slowing RCC progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Renal Cell / genetics
  • Carcinoma, Renal Cell / metabolism*
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation*
  • Chemokine CXCL5 / genetics
  • Chemokine CXCL5 / metabolism*
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Humans
  • Kidney Neoplasms / genetics
  • Kidney Neoplasms / metabolism*
  • Kidney Neoplasms / pathology
  • Mice
  • NF-kappa B / genetics
  • NF-kappa B / metabolism*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Signal Transduction*
  • Tumor Microenvironment*

Substances

  • CXCL5 protein, human
  • Chemokine CXCL5
  • NF-kappa B
  • Receptors, Androgen
  • Proto-Oncogene Proteins c-akt