title: Oleanolic acid induces migration in Mv1Lu and MDA-MB-231 epithelial cells involving EGF receptor and MAP kinases activation.
abstract: During wound healing, skin function is restored by the action of several cell types that undergo differentiation, migration, proliferation and/or apoptosis. These dynamics are tightly regulated by the evolution of the extra cellular matrix (ECM) contents along the process. Pharmacologically active flavonoids have shown to exhibit useful physiological properties interesting in pathological states. Among them, oleanolic acid (OA), a pentacyclic triterpene, shows promising properties over wound healing, as increased cell migration in vitro and improved wound resolution in vivo. In this paper, we pursued to disclose the molecular mechanisms underlying those effects, by using an in vitro scratch assay in two epithelial cell lines of different linage: non-malignant mink lung epithelial cells, Mv1Lu; and human breast cancer cells, MDA-MB-231. In every case, we observed that OA clearly enhanced cell migration for in vitro scratch closure. This correlated with the stimulation of molecular pathways related to mitogen-activated protein (MAP) kinases, as ERK1,2 and Jun N-terminal kinase (JNK) 1,2 activation and c-Jun phosphorylation. Moreover, MDA-MB-231 cells treated with OA displayed an altered gene expression profile affecting transcription factor genes (c-JUN) as well as proteins involved in migration and ECM dynamics (PAI1), in line with the development of an epithelial to mesenchymal transition (EMT) status. Strikingly, upon OA treatment, we observed changes in the epidermal growth factor receptor (EGFR) subcellular localization, while interfering with its signalling completely prevented migration effects. This data provides a physiological framework supporting the notion that lipophilic plant extracts used in traditional medicine, might modulate wound healing processes in vivo through its OA contents. The molecular implications of these observations are discussed.
authors.affiliation: Laboratorio de Oncología Molecular y TGF-ß, Instituto Murciano de Investigaciones Biosanitarias-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Bernabé-García
authors.affiliation: Departamento de Enfermería, Facultad Enfermería, Universidad de Murcia, Murcia, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Armero-Barranco
authors.affiliation: Laboratorio de Oncología Molecular y TGF-ß, Instituto Murciano de Investigaciones Biosanitarias-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Liarte
authors.affiliation: Departamento de Enfermería, Facultad Enfermería, Universidad de Murcia, Murcia, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Ruzafa-Martínez
authors.affiliation: Departamento de Enfermería, Facultad Enfermería, Universidad de Murcia, Murcia, Spain.
authors.forename: Antonio Jesús
authors.initials: AJ
authors.lastname: Ramos-Morcillo
authors.affiliation: Laboratorio de Oncología Molecular y TGF-ß, Instituto Murciano de Investigaciones Biosanitarias-Arrixaca, Hospital Clínico Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain.
authors.forename: Francisco José
authors.identifier: http://orcid.org/0000-0002-3969-1430
authors.initials: FJ
authors.lastname: Nicolás
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009828:Oleanolic Acid / Q000494:pharmacology*
chemical_list: D020536:Enzyme Activators; D009828:Oleanolic Acid; C512478:EGFR protein, human; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4