Type I Collagen Receptor (α2β1) Signaling Promotes Prostate Cancer Invasion through RhoC GTPase

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.