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.