Type I Collagen Receptor (alpha2beta1) Signaling Promotes Prostate Cancer Invasion Through RhoC GTPase

Neoplasia. 2008 Aug;10(8):797-803. doi: 10.1593/neo.08380.

Abstract

The most frequent site of metastasis in human prostate cancer (PCa) is the bone. Preferential adhesion of PCa cells to bone-specific factors may facilitate the selective metastasis of the skeleton. The most abundant protein within the skeleton is type I collagen. We previously demonstrated that PCa cells selected in vitro for collagen I binding (LNCaP(col)) are highly motile and acquired the capacity to grow within the bone compared to nontumorigenic LNCaP parental cells. Treatment with alpha(2)beta(1)-neutralizing antibodies selectively blocked collagen-stimulated migration, suggesting that integrin signaling mediates PCa migration. To elucidate the mechanism of collagen-stimulated migration, we evaluated integrin-associated signaling pathways in non-collagen-binding LNCaP parental cells and in collagen-binding isogenic C4-2B and LNCaP(col) PCa cells. The expression and activity of RhoC guanosine triphosphatase was increased five- to eightfold in collagen-binding LNCaP(col) and C4-2B cells, respectively, compared to parental LNCaP cells. RhoC activation was selectively blocked with antibodies to alpha(2)beta(1) where treatment with a small hairpin RNA specific for RhoC suppressed collagen-mediated invasion without altering the PCa cells' affinity for collagen I. We conclude that the ligation of alpha(2)beta(1) by collagen I activates RhoC guanosine triphosphatase, which mediates PCa invasion, and suggests a mechanism for the preferential metastasis of PCa cells within the bone.

Publication types

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

MeSH terms

  • Antibodies / pharmacology
  • Antigen-Antibody Reactions
  • Cell Line, Tumor
  • Collagen Type I / antagonists & inhibitors
  • Collagen Type I / metabolism*
  • Collagen Type I / pharmacology
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Humans
  • Immunoglobulin G / pharmacology
  • Integrin alpha2beta1 / drug effects
  • Integrin alpha2beta1 / metabolism*
  • Male
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology
  • Protein Binding
  • Signal Transduction*
  • rho GTP-Binding Proteins / drug effects
  • rho GTP-Binding Proteins / metabolism*

Substances

  • Antibodies
  • Collagen Type I
  • Immunoglobulin G
  • Integrin alpha2beta1
  • rho GTP-Binding Proteins