1. Carcinogenesis. 2012 Jan;33(1):164-73. doi: 10.1093/carcin/bgr240. Epub 2011 Oct 31.
DHA induces apoptosis and differentiation in human melanoma cells in vitro: involvement of HuR-mediated COX-2 mRNA stabilization and β-catenin nuclear translocation.
Serini S(1), Fasano E, Piccioni E, Monego G, Cittadini AR, Celleno L, Ranelletti FO, Calviello G.
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 cellline showed a constitutive COX-2 expression higher than that of the primary WM115cells, an increased cytosolic level of the COX-2 messenger RNA (mRNA)-stabilizer human antigen R (HuR) and a lower susceptibility to basal apoptosis. Thetransfection 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-3polyunsaturated 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 andstability 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. PMID: 22045024 [PubMed - indexed for MEDLINE]