CONICET | Buscador de Institutos y Recursos Humanos

Melanoma is the most aggressive type of skin cancer and constitutes one of the most common causes of cancer death in individuals between 20 and 35 years of age, which generates a socioeconomic impact. Although recent therapies have shown an impressive success, unfortunately patients develop resistance after a short period of disease control. Autophagy has been indicated as a possible mechanism of resistance in tumor cells, which favors their survival and metastasis. Autophagy is a process regulated by numerous factors, including hypoxia, a distinctive feature of the tumor microenvironment, and sphingosine-1-phosphate (S1P), a bioactive lipid with important functions in cancer and inflammation. Recently, our group has shown that Filamin-A (FLNa), an actin binding protein, reduces the activation of the PI3K / Akt pathway and the migration of melanoma cells in the presence of S1P, depending on the expression and activation of its receptors (S1PR), mainly S1PR1, S1PR2 and S1PR3. Our hypothesis is that FLNa positively regulates autophagy and tumor survival induced by S1P and hypoxia. To this end, we explored some biological actions triggered by culturing two melanoma cells, M2 cells (FLNa-) and A7 cells (FLNa+), in hypoxia (1% O2) or normoxia (21% O2) and treated them with or without extracellular S1P (100 nM). We observed that, compared to normoxia, hypoxia significantly increased the LC3II levels only in A7 cells. Mechanistically, FLNa expression is required for activation and nuclear translocation of HIF-1, which in turn support the autophagic process. Furthermore, S1P showed a synergistic effect with hypoxia to induce autophagy only on FLNA+ cells, suggesting that FLNa could regulate this process through different pathways. These results suggest that FLNa is a key protein in the autophagy induced by hypoxia and S1P present on the tumoral microenvironment.