PDE4D promotes FAK-mediated cell invasion in BRAF-mutated melanoma.
Fiche publication
Date publication
juin 2017
Journal
Oncogene
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BENSUSSAN Armand
Tous les auteurs :
Delyon J, Servy A, Laugier F, André J, Ortonne N, Battistella M, Mourah S, Bensussan A, Lebbé C, Dumaz N
Lien Pubmed
Résumé
The cyclic AMP (cAMP) signaling pathway is critical in melanocyte biology for regulating differentiation. It is downregulated by phosphodiesterase (PDE) enzymes, which degrade cAMP itself. In melanoma evidence suggests that inhibition of the cAMP pathway by PDE type 4 (PDE4) favors tumor progression. For example, in melanomas harboring RAS mutations, the overexpression of PDE4 is crucial for MAPK pathway activation and proliferation induced by oncogenic RAS. Here we showed that PDE4D is overexpressed in BRAF-mutated melanoma cell lines, constitutively disrupting the cAMP pathway activation. PDE4D promoted melanoma invasion by interacting with focal adhesion kinase (FAK) through the scaffolding protein RACK1. Inhibition of PDE4 activity or inhibition of PDE4D interaction with FAK reduced invasion. PDE4D expression is increased in patients with advanced melanoma and PDE4D-FAK interaction is detectable in situ in metastatic melanoma. Our study establishes the role of PDE4D in BRAF-mutated melanoma as regulator of cell invasion, and suggests its potential as a target for preventing metastatic dissemination.
Mots clés
Apoptosis, Biomarkers, Tumor, genetics, Cell Differentiation, Cell Movement, Cell Proliferation, Cyclic Nucleotide Phosphodiesterases, Type 4, genetics, Focal Adhesion Kinase 1, genetics, Humans, Melanocytes, cytology, Melanoma, genetics, Mutation, genetics, Neoplasm Invasiveness, Neoplasm Staging, Phosphorylation, Prognosis, Proto-Oncogene Proteins B-raf, genetics, Signal Transduction, Tumor Cells, Cultured
Référence
Oncogene. 2017 06 8;36(23):3252-3262