SPHINGOSINE-1-PHOSPHATE PROMOTES A MIGRATORY PHENOTYPE OF MELANOMA CELLS IN HYPOXIA

PEREZ C; CASTRO M; CAMPOS L; RODRIGUEZ Y; RAMIREZ, DC; ALVAREZ SE

Buenos Aires

Congreso; Reunion Conjunta de Sociedades de Neurociencias; 2017

Melanoma is the most aggressive type of skin cancer with a high mortality percentage. Half of melanoma patients display the mutation V600E in the BRAF protein kinase. Indeed, FDA and ANMAT have approved the use of Vemurafenib and Dabrafenib (BRAF inhibitors) in melanoma patients. Unfortunately, patients develop resistance after a short period of disease control, indicating that new targets are needed. In that regard, several evidences confirm that tumor microenvironment modulates proliferation, migration and acquired resistance of cancer. Precisely, hypoxia is a remarkable feature of the tumor microenvironment and controls cancer growth and progression. On the other hand, the bioactive sphingolipid sphingosine-1-phosphate (S1P) has been linked to multiple mechanisms leading to chronic inflammation and cancer. Thus, the aim of this study was to elucidate how hypoxia and S1P influence the viability and migration of melanoma cells. To this end, we used two melanoma cell lines: SkMel2 (BRAFWT) and Lu1205 (BRAFV600E). Viability was studied by MTT and migration analyzed by Wound Healing Assay. Hypoxia augments the viability and reduces apoptosis of melanoma cells cultured in serum-withdrawal conditions but does not affect cell migration. On the other hand, S1P has no effect on cell viability in hypoxia, but stimulates the migration of Lu1205 melanoma cells through engagement of S1PR1 and S1PR3 receptors, suggesting that the sphingolipid promotes a migratory and invasive phenotype when oxygen levels and nutrients availability are low. In addition, inhibition of BRAF with Vemurafenib diminishes S1P-induced migration in hypoxia. Altogether, these results suggest that hypoxia protects melanoma cells from the apoptosis induced by growth factor?s shortage. In addition, the presence of S1P in the tumor microenvironment is critical for establishing a migratory phenotype on melanoma cells.