title: Retinoic acid induces nuclear FAK translocation and reduces breast cancer cell adhesion through Moesin, FAK, and Paxillin.
abstract: Breast cancer is the most common malignancy in women, with metastases being the cause of death in 98%. In previous works we have demonstrated that retinoic acid (RA), the main retinoic acid receptor (RAR) ligand, is involved in the metastatic process by inhibiting migration through a reduced expression of the specific migration-related proteins Moesin, c-Src, and FAK. At present, our hypothesis is that RA also acts for short periods in a non-genomic action to cooperate with motility reduction and morphology of breast cancer cells. Here we identify that the administration of 10(-6) M RA (10-20 min) induces the activation of the migration-related proteins Moesin, FAK, and Paxillin in T-47D breast cancer cells. The phosphorylation exerted by the selective agonists for RARα and RARβ, on Moesin, FAK, and Paxillin was comparable to the activation exerted by RA. The RARγ agonist only led to a weak activation, suggesting the involvement of RARα and RARβ in this pathway. We then treated the cells with different inhibitors that are involved in cell signaling to regulate the mechanisms of cell motility. RA failed to activate Moesin, FAK, and Paxillin in cells treated with Src inhibitor (PP2) and PI3K inhibitor (WM), suggesting the participation of Src-PI3K in this pathway. Treatment with 10(-6) M RA for 20 min significantly decreased cell adhesion. However, when cells were treated with 10(-6) M RA and FAK inhibitor, the RA did not significantly inhibit adhesion, suggesting a role of FAK in the adhesion inhibited by RA. By immunofluorescence and immunoblotting analysis we demonstrated that RA induced nuclear FAK translocation leading to a reduced cellular adhesion. These findings provide new information on the actions of RA for short periods. RA participates in cell adhesion and subsequent migration, modulating the relocation and activation of proteins involved in cell migration.
authors.affiliation: Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Research Council of Argentina, Mendoza, Argentina.
authors.forename: Angel Matías
authors.initials: AM
authors.lastname: Sanchez
authors.affiliation: Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Research Council of Argentina, Mendoza, Argentina.
authors.forename: Jorge Eduardo
authors.initials: JE
authors.lastname: Shortrede
authors.affiliation: Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Research Council of Argentina, Mendoza, Argentina; School of Medical Sciences, National University of Cuyo, Mendoza, Argentina.
authors.forename: Laura María
authors.initials: LM
authors.lastname: Vargas-Roig
authors.affiliation: Institute of Medicine and Experimental Biology of Cuyo (IMBECU), National Research Council of Argentina, Mendoza, Argentina. Electronic address: mflamini@mendoza-conicet.gob.ar.
authors.forename: Marina Inés
authors.initials: MI
authors.lastname: Flamini
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D050884:HSP72 Heat-Shock Proteins; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D051419:Paxillin / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D021381:Protein Transport / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D055551:HSP27 Heat-Shock Proteins; D050884:HSP72 Heat-Shock Proteins; D008840:Microfilament Proteins; D051419:Paxillin; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D016159:Tumor Suppressor Protein p53; C082925:retinoic acid receptor beta; C071058:moesin; D014212:Tretinoin; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases
keywords: Breast cancer cells; Cell adhesion/migration; FAK; Moesin; Paxillin; Retinoic acid