title: DHA induces apoptosis and differentiation in human melanoma cells in vitro: involvement of HuR-mediated COX-2 mRNA stabilization and β-catenin nuclear translocation.
abstract: The pro-inflammatory phenotype accompanying melanoma progression includes an enhanced expression of cyclooxygenase-2 (COX-2), which plays an important role in the acquisition of apoptosis resistance, and is a suitable target for melanoma prevention and therapy. We observed that the WM266-4 metastatic melanoma cell line showed a constitutive COX-2 expression higher than that of the primary WM115 cells, an increased cytosolic level of the COX-2 messenger RNA (mRNA)-stabilizer human antigen R (HuR) and a lower susceptibility to basal apoptosis. The transfection of HuR siRNA induced apoptosis and reduced COX-2 protein abundance in both the cells. The same effects were observed treating the cells with the n-3 polyunsaturated fatty acid docosahexaenoic acid (DHA), which reduced the cytoplasmic location and expression of HuR and, correspondently, decreased COX-2 protein expression and induced apoptosis. DHA also decreased the expression and stability of COX-2 mRNA, increased the β-catenin expression in the nuclei and reduced it in the cytosol, where it forms a complex with HuR and COX-2 mRNA. DHA had also a pro-differentiating effect, which is compatible with the nuclear translocation of β-catenin. These findings allow us to associate for the first time the constitutive expression of COX-2 in melanoma cells to the HuR-mediated stabilization of its mRNA and suggest that also β-catenin may play a role in HuR-mediated COX-2 stabilization in these cells. The data demonstrate that the HuR-mediated stabilization of COX-2 may represent a target of DHA action in melanoma cells and suggest the application of DHA in the prevention and therapy of melanoma.
authors: Institute of General Pathology, Università Cattolica del Sacro Cuore, Largo F. Vito, 1 - 00168 Rome, Italy.
authors: Simona
authors: S
authors: Serini
authors: Elena
authors: E
authors: Fasano
authors: Elisabetta
authors: E
authors: Piccioni
authors: Giovanni
authors: G
authors: Monego
authors: Achille R M
authors: AR
authors: Cittadini
authors: Leonardo
authors: L
authors: Celleno
authors: Franco O
authors: FO
authors: Ranelletti
authors: Gabriella
authors: G
authors: Calviello
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D051959:ELAV Proteins / Q000502:physiology*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D020871:RNA Stability; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051959:ELAV Proteins; D051176:beta Catenin; D004281:Docosahexaenoic Acids; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human