RESVERATROL ALTERS SPHINGOLIPID METABOLISM IN RAS-TRANSFORMED 3T3 FIBROBLASTS

The effect of resveratrol on the sphingolipid metabolism has been investigated in ras-transformed 3T3 fibroblasts. Resveratrol is a phytoalexin of a great medico-biological significance, which has been reported to exhibit significant beneficial effects such as antioxidant, lipid-lowering, anti-neoplastic, etc. Sphingolipids are functionally active lipid molecules, which are implicated in important cellular processes, such as proliferation, migration, apoptosis and transmembrane signalling, among others. Although there are many investigations devoted to the influence of resveratrol on the lipid metabolism of various types of cancer cells, the mechanism of this effect on the sphingolipid pathway remains unclear. The present studies showed that the major sphingolipid, sphingomyelin, was decreased in membranes from resveratrol-treated ras-transformed 3T3 fibroblasts, whereas ceramide, which is a pro-apoptotic factor, was elevated due to neutral sphingomyelinase up-regulation. In addition, the level of sphingosine, a product of ceramidase, was increased and the content of sphingosine-1-phosphate, which is related to cell proliferation, was lowered due to resveratrol treatment, which is an important finding especially for cancer cells. The balancing enzyme in the sphingolipid pathway, sphingosine kinase, which produces sphingosine-1-phosphate, was down-regulated in resveratrol-treated oncogene-transformed fibroblasts. In conclusion, the present results clearly show that treatment of ras-transformed fibroblasts with resveratrol induces changes in the major representatives of the sphingolipid metabolic pathway shifting the "sphingolipid rheostat" towards prevalence of the proapoptotic factor ceramide. The reported observations can be applied in the development of complex anti-tumour therapeutic strategies.