Role of stearoyl-CoA desaturase in cell proliferation and survival and in tumorigenic capacity of human neoplastic cells

N. SCAGLIA; R. A. IGAL

Congreso; Gordon Research Conferences. Molecular & Cellular Biology of Lipids; 2005

Saturated and monounsaturated fatty acids are the most abundant fatty acid species in mammalian organisms and their distribution is regulated by stearoyl-CoA desaturase, the enzyme that converts saturated into monounsaturated fatty acids. A positive correlation between high monounsaturated fatty acid levels and neoplastic transformation has been reported, but little is still known about the regulation of stearoyl-CoA desaturase in cell proliferation and apoptosis, as well as in cancer development. Here we report that simian virus 40-transformed human lung fibroblasts bearing a knockdown of human stearoyl-CoA desaturase by stable antisense cDNA transfection (hSCDas cells) showed a considerable reduction in monounsaturated fatty acids, cholesterol and phospholipid synthesis, compared to empty vector transfected-simian virus 40 cell line (control cells). hSCDas cells also exhibited high cellular levels of saturated free fatty acids and triacylglycerol. Interestingly, stearoyl-CoA desaturase-depleted cells exhibited a dramatic decrease in proliferation rate and abolition of anchorage-independent growth. Prolonged exposure to exogenous oleic acid did not reverse either the slower proliferation or loss of anchorage-independent growth of hSCDas cells, suggesting that endogenous synthesis of monounsaturated fatty acids is essential for rapid cell replication and invasiveness, two hallmarks of neoplastic transformation. Moreover, apoptosis was increased in hSCDas cells in a ceramide-independent manner. In addition, the impact of SCD deficiency on tumor formation was analyzed in human lung adenocarcinoma A549 cells bearing a stable knockdown of SCD and in A549 cells transfected with empty expression vector. To do so, cells from both groups were injected subcutaneously into athymic ?nude? mice and tumor growth was followed during 4 months. It was observed that mice injected with mock-transfected A549 cells developed visible tumors after two weeks whereas SCD-deficient A549 cells produced visible tumor formations only after two months of cell injection. This observation suggests that the lack of SCD promotes a delay in tumor formation but not the total suppression of tumor growth. Altogether, our data suggest that, by globally regulating lipid metabolism, stearoyl-CoA desaturase activity modulates cell proliferation and survival, and emphasize the important role of endogenously synthesized monounsaturated fatty acids in sustaining the neoplastic phenotype of transformed cells.