title: Type I collagen receptor (alpha2beta1) 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.
authors.affiliation: Department of Urology, The University of Michigan, Ann Arbor, MI 48109-0940, USA. clhall@umich.edu
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Hall
authors.forename: Cara W
authors.initials: CW
authors.lastname: Dubyk
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Riesenberger
authors.forename: Daniel
authors.initials: D
authors.lastname: Shein
authors.forename: Evan T
authors.initials: ET
authors.lastname: Keller
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: van Golen
mesh_terms: 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*
chemical_list: D000906:Antibodies; D024042:Collagen Type I; D007074:Immunoglobulin G; D038982:Integrin alpha2beta1; D020741:rho GTP-Binding Proteins