New Type of Antitumor Agent Targeting the Cell Adhesion Molecule, Integrin.
The extracellular matrix (ECM) provides a variety of biological signals for cell regulation. It is apparent that some of these signals are derived from functional sites, which are concealed in the higher structure of ECM protein molecules. Previously, we found that fibronectin, a ubiquitous cell adhesive ECM protein, harbors a cryptic functional site termed FNIII14, which can be exposed through the processing of fibronectin by inflammatory proteinases, including matrix metalloproteinase-2 (MMP-2). FNIII14, once exposed, induces a conformational change in beta1-integrins necessary for their functional inactivation, resulting in weakened cell adhesion to the ECM. Interestingly, eukaryotic peptide elongation factor 1A (eEF1A) was recently identified as a membrane receptor mediating this anti-adhesive effect of FNIII14. Here, we show that exposure of FNIII14 from the fibronectin matrix, and its interaction with the membrane receptor eEF1A, contributes to the migration and invasion of cancer cells. Furthermore, an in vivo experiment using a mouse xenograft model shows that FNIII14 could be a promising target for preventing lung metastasis of melanoma.
Department of Molecular Patho-Physiology, Faculty of Pharmaceutical Sciences, Tokyo University of Science.
Fumio
F
Fukai
D000818:Animals; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D055808:Drug Discovery / Q000639:trends*; D005109:Extracellular Matrix; D005353:Fibronectins; D016023:Integrins; D020778:Matrix Metalloproteinase 2; D051379:Mice; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D020648:Peptide Elongation Factor 1
D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; C094814:EEF1A1 protein, human; C067625:FN1 protein, human; D005353:Fibronectins; D016023:Integrins; D020648:Peptide Elongation Factor 1; D020778:Matrix Metalloproteinase 2