RESUMO
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 αvß3 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 GSK3ß 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.
Assuntos
Colágeno/metabolismo , Colágenos Associados a Fibrilas/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Integrina alfaVbeta3/metabolismo , Melanoma/enzimologia , Fragmentos de Peptídeos/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/enzimologia , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases Dependentes de 3-Fosfoinositídeo/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Colágeno/farmacologia , Colágenos Associados a Fibrilas/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Integrina alfaVbeta3/efeitos dos fármacos , Melanoma/tratamento farmacológico , Melanoma/patologia , Terapia de Alvo Molecular , Fragmentos de Peptídeos/farmacologia , Fosforilação , Domínios Proteicos , Transdução de Sinais/efeitos dos fármacos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologiaRESUMO
During tumor invasion, tumor cells degrade the extracellular matrix. Basement membrane degradation is responsible for the production of peptides with anti-tumor properties. Type XIX collagen is associated with basement membranes in vascular, neuronal, mesenchymal and epithelial tissues. Previously, we demonstrated that the non-collagenous NC1, C-terminal, domain of collagen XIX [NC1(XIX)] inhibits the migration capacities of tumor cells and exerts a strong inhibition of tumor growth. Here, we demonstrate that plasmin, one of the most important enzyme involved in tumor invasion, was able to release a fragment of NC1(XIX), which retained the anti-tumor activity. Molecular modeling studies showed that NC1(XIX) and the anti-tumor fragment released by plasmin (F4) adopted locally the same type I ß-turn conformation. This suggests that the anti-tumor effect is conformation-dependent. This study demonstrates that collagen XIX is a novel proteolytic substrate for plasmin. Such release may constitute a defense of the organism against tumor invasion.
