Type I collagen receptor (alpha2beta1) signaling promotes prostate cancer invasion through RhoC GTPase.
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.
Hall
Christopher L
CL
Department of Urology, The University of Michigan, Ann Arbor, MI 48109-0940, USA. clhall@umich.edu
Dubyk
Cara W
CW
Riesenberger
Tracy A
TA
Shein
Daniel
D
Keller
Evan T
ET
van Golen
Kenneth L
KL
D000906:Antibodies / Q000494:pharmacology; D000937:Antigen-Antibody Reactions; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D038982:Integrin alpha2beta1 / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D015398:Signal Transduction; D020741:rho GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism*
D000906:Antibodies; D024042:Collagen Type I; D007074:Immunoglobulin G; D038982:Integrin alpha2beta1; D020741:rho GTP-Binding Proteins