The anti-tumor NC1 domain of collagen XIX inhibits the FAK/ PI3K/Akt/mTOR signaling pathway through αvβ3 integrin interaction.

// Jean-Baptiste Oudart 1, 2 , Manon Doue 1 , Alexia Vautrin 1 , Bertrand Brassart 1 , Christele Sellier 1 , Aurelie Dupont-Deshorgue 1 , Jean-Claude Monboisse 1, 2 , Francois-Xavier Maquart 1, 2 , Sylvie Brassart-Pasco 1 , Laurent Ramont 1, 2 1 Universite de Reims Champagne-Ardenne, CNRS UMR 7369 (Matrice Extracellulaire et Dynamique Cellulaire, MEDyC), Reims, France 2 CHU de Reims, Laboratoire Central de Biochimie, Reims, France Correspondence to: Laurent Ramont, e-mail: lramont@chu-reims.fr Keywords: collagen XIX, NC1 domain, integrin, FAK/PI3K/Akt/mTOR, tumor invasion Received: April 24, 2015      Accepted: November 14, 2015      Published: November 26, 2015 ABSTRACT Type XIX collagen is a minor collagen associated with basement membranes. It was isolated for the first time in a human cDNA library from rhabdomyosarcoma and belongs to the FACITs family (Fibril Associated Collagens with Interrupted Triple Helices). Previously, we demonstrated that the NC1 domain of collagen XIX (NC1(XIX)) exerts anti-tumor properties on melanoma cells by inhibiting their migration and invasion. In the present work, we identified for the first time the integrin αvβ3 as a receptor of NC1(XIX). Moreover, we demonstrated that NC1(XIX) inhibits the FAK/PI3K/Akt/mTOR pathway, by decreasing the phosphorylation and activity of the major proteins involved in this pathway. On the other hand, NC1(XIX) induced an increase of GSK3β activity by decreasing its degree of phosphorylation. Treatments targeting this central signaling pathway in the development of melanoma are promising and new molecules should be developed. NC1(XIX) seems to have the potential for the design of new anti-cancer drugs.