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

YAMILA I RODRIGUEZ; CELIA NOEMÍ PEREZ; SERGIO ALVAREZ; LUDMILA E CAMPOS; DARIO RAMIREZ; MELINA GABRIELA CASTRO

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Melanoma is the most aggressive type of skin cancer with a highmortality percentage. Half of melanoma patients display the mutationV600E in the BRAF protein kinase. Indeed, FDA and ANMAThave approved the use of Vemurafenib and Dabrafenib (BRAF inhibitors)in melanoma patients. Unfortunately, patients develop resistanceafter a short period of disease control, indicating that newtargets are needed. In that regard, several evidences confirm thattumor microenvironment modulates proliferation, migration and acquiredresistance of cancer. Precisely, hypoxia is a remarkable featureof the tumor microenvironment and controls cancer growth andprogression. On the other hand, the bioactive sphingolipid sphingosine-1-phosphate (S1P) has been linked to multiple mechanismsleading to chronic inflammation and cancer. Thus, the aim of thisstudy was to elucidate how hypoxia and S1P influence the viabilityand migration of melanoma cells. To this end, we used two melanomacell lines: SkMel2 (BRAFWT) and Lu1205 (BRAFV600E). Viabilitywas studied by MTT and migration analyzed by Wound HealingAssay. Hypoxia augments the viability and reduces apoptosis ofmelanoma cells cultured in serum-withdrawal conditions but doesnot affect cell migration. On the other hand, S1P has no effect oncell viability in hypoxia, but stimulates the migration of Lu1205 melanomacells through engagement of S1PR1 and S1PR3 receptors,suggesting that the sphingolipid promotes a migratory and invasivephenotype when oxygen levels and nutrients availability are low. Inaddition, inhibition of BRAF with Vemurafenib diminishes S1P-inducedmigration in hypoxia. Altogether, these results suggest thathypoxia protects melanoma cells from the apoptosis induced bygrowth factor?s shortage. In addition, the presence of S1P in thetumor microenvironment is critical for establishing a migratory phenotypeon melanoma cells