Comunicación

OLEANOLIC ACID STIMULATION OF CELL MIGRATION INVOLVES A COMPLEX BIPHASIC MECHANISM

Autores:

Javier Stelling Férez1, FRANCISCO JOSE NICOLAS VILLAESCUSA2, José Antonio Gabaldón Hernández3

Afiliaciones:

(1) Unidad de Investigación - Laboratorio de Regeneración, Oncología Molecular y TGFß, 30507, España (Región de Murcia)
(2) TRASPLANTE HEMATOPOYÉTICO / TERAPIA CELULAR, IMIB-Arrixaca, España
(3) Reconocimiento y encapsulación molecular, Departamento de Nutrición y Tecnología de los Alimentos, UCAM, 30107, España (Región de Murcia)

Comunicación:

Antecedentes:

Epithelial cell migration is essential for wound closure and skin restoration. Triterpenoids, particularly oleanolic acid (OA), have shown wound healing properties. Previously we studied the molecular mechanisms that are activated by this molecule, involving c-Jun terminal kinase (JNK) and MAP kinases (MEK, ERK) activation, showing a similar effect to epidermal growth factor (EGF). Indeed, OA stimulation produces the Epidermal growth factor (EGFR) phosphorylation, which leads into c-Jun stimulation, a master regulator for wound healing. However, the precisely OA target in this system are not yet clear. We decided to go deeply into these mechanisms to unravel new OA targets and stimulated pathways.

Métodos:

We have studied OA-triggered molecular mechanisms in two epithelial cell lines: Mv1Lu and MDA-MB-231, by using in vitro front migration assays. These assays are followed by pro-migratory proteins expression analysis and the study of its subcellular localization.

Resultados:

We have shown that OA induces the activation, at cells of the wound edge, of c-Jun. On top of that, cell migration is mediated by dynamic changes in cell architecture: cytoskeleton reorganization and focal adhesion (FA) remodeling. Thus, we have shown that OA activates focal adhesion kinase (FAK), a critical factor for FA remodeling. Furthermore, OA changes the distribution of paxillin and actin in migrating cells, promoting a dynamic cell architecture. The study of different signaling kinases inhibitors (MEK, JNK, EGFR) had been used to dissect the contribution of different pathways induced by OA during migration. In this sense, in the presence of OA, key elements such as c-Jun transcription factor, are activated at different times to EGFR. activated by a different pathway from EGFR. In contrast, OA-activation of FAK, is dependent on and it is spatially linked to EGFR. The molecular implications behind these process are discussed.

Conclusiones:

• OA induces c-Jun expression and phosphorylation in the cells at wound edge of front migration assays. • OA stimulated EGFR and c-Jun display a different phosphorylation dynamic. OA induction on c-Jun occurs by an independent pathway from EGFR, revealed by EGFR (PD153035) inhibitor and timing experiments. • OA promotes changes in actin fibers and paxillin distribution, FAK activation and consequently focal adhesion remodeling. • FAK activation by OA is prevented by EGFR inhibitor and MEK inhibitor. • All these data strongly suggest a biphasic molecular mechanism induced by OA and integrated by EGFR/FAK/ERK axis and MEK/JNK/c-Jun axis.


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Dirección

Campus de Ciencias de la Salud
Carretera Buenavista s/n, 30120 El Palmar
Murcia, España

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