Caveolin-1 regulates VEGF-stimulated angiogenic activities in prostate cancer and endothelial cells

Abstract

Caveolin-1 (cav-1) is a multifunctional protein and major component of caveolae membranes serving important functions related to signal transduction, endocytosis, transcytosis, and molecular transport. We previously showed that cav-1 is overexpressed and secreted by metastatic prostate cancer cells. We now report that cav-1 gene transduction (Aadcav-1) or recombinant cav-1 (rcav-1) protein treatment of cav-1-negative prostate cancer cell line LPp-LNCaPp or cav-1-/- endothelial cells potentiated VEeGF-stimulated angiogenic signaling.Downregulation of cav-1 in prostate cancer cell line PpC-3 or human umbilical vein endothelial cells (HhUVEeCs) through cav-1 siRNA significantly reduced basal and VEGF-stimulated phosphorylation of VEGFR2 (Y951), PLCγ1 (Y783) and/or Aakt (Ss473 & T308) relative to those in control siRNAa treated cells. Aadditionally rcav-1 stimulation of cav-1 siRNAa treated HhUVEeCs restored this signaling pathway. Confocal microscopy and immunoprecipitation analysis revealed association and colocalization of VEeGFR2 and PpLCγ1 with cav-1 following VEeGF stimulation in HhUVEeCs. Interestingly, treatment of HUVECs with cav-1 scaffolding domain (CSD) caused significant reduction in the VEGF-stimulated phosphorylation of VEeGFR2, and suggesting that CSsD inhibits cav-1-mediated angiogenic signaling. VEeGF stimulation of significantly increased tubule length and cell migration, but this stimulatory effect was significantly reduced by cav-1 siRNA and/or CSsD treatment. The present study demonstrates that cav-1 regulates VEeGF-stimulated VEeGFR2 autophosphorylation and activation of downstream angiogenic signaling, possibly through compartmentalization of specific signaling molecules. Our results provide mechanistic insight into the role of cav-1 in prostate cancer and suggest the use of CSsD as a therapeutic tool to suppress angiogenic signaling in prostate cancer. © 2009 Landes Bioscience.