Retinoic acid induces nuclear FAK translocation and reduces breast cancer cell adhesion through Moesin, FAK, and Paxillin

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• 作者：Angel Matí ; as Sanchez^a ; Jorge Eduardo Shortrede^a ; Laura Marí ; a Vargas-Roig^a ; ^b ; Marina Iné ; s Flamini^a ; ^{mflamini@mendoza-conicet.gob.ar" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Retinoic acid ; Moesin ; FAK ; Paxillin ; Cell adhesion/migration ; Breast cancer cells
• 刊名：Molecular and Cellular Endocrinology
• 出版年：2016
• 出版时间：15 July 2016
• 年：2016
• 卷：430
• 期：Complete
• 页码：1-11
• 全文大小：2989 K

文摘

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.