Stearoyl-CoA Desaturase Is Involved in the Control of Proliferation,Anchorage-independent Growth, and Survival in Human TransformedCells

Abstract

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 with 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 ceramideindependent manner. Finally, stearoyl-CoA desaturasedeficient cells were more sensitive to palmitic acidinduced apoptosis compared with control cells. 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.

Stearoyl CoA desaturase 1 is elevated in obesity but protects against fatty acid-induced skeletal muscle insulin resistance in vitro

“…Although our findings of a protective role of SCD1 are consistent with data on other cell types [17,18,38], some authors [29] have suggested that elevated skeletal muscle SCD1 expression contributes to abnormal lipid metabolism and the aetiology of obesity. In this previous study [29], SCD1 overexpression decreased fatty acid oxidation and increased triacylglycerol synthesis.…”

“…In this previous study [29], SCD1 overexpression decreased fatty acid oxidation and increased triacylglycerol synthesis. While our data largely support these observations, triacylglycerol accumulation per se is unlikely to cause insulin resistance [39] or lipotoxicity [17,18,38], and in fact may provide protection by providing a reservoir for the deposition of other fatty acyl-CoA metabolites. Importantly, our data add to these previous observations and indicate that triacylglycerol accumulation in SCD1-overexpressing cells protects cells from DAG and ceramide accumulation.…”

“…They do, however, indicate that SCD1 protects muscle cells from fatty acid-induced insulin resistance by reducing ceramide and DAG accumulation. This interpretation supports studies in beta cells, lung fibroblasts and Chinese hamster ovary cells [17,18,38] that describe a role for SCD1 in protection against the toxic effects of palmitate and support the model of cellular lipid metabolism, in which triacylglycerol accumulation protects against lipotoxicity. p<0.05 vs L6 (n=8)…”

“…The quantity and distribution of saturated and unsaturated fatty acids affects many cellular processes, including phospholipid composition and membrane fluidity, the generation of second messengers in signalling cascades, metabolic fuel storage in the form of triacylglycerols, cellular differentiation, and apoptosis [17][18][19][20]. With reference to insulin resistance, recent studies have indicated that exposure of skeletal muscle to excess saturated fatty acid results in the generation of the fatty acyl-CoA metabolites diacylglycerol (DAG) and ceramide, which interfere directly with insulin signal transduction [7][8][9][10][11][12][13].…”

Metformin and Pancreatic Cancer Metabolism

“…Indeed, Moore and others speculated that the down-regulation of SCD cDNA in prostate carcinoma may be due to: a) the need of the cancer cell to increase the levels of palmitate which can be done by decreasing SCD activity, b) eliminate the SCD-induced down-regulation of lipid membrane rafts and c) down-regulate susceptibility of tumor cells containing more unsaturated fatty acids to TNF-induced free radical attack [113]. Nevertheless, knockdown of human SCD in transformed human fibroblasts resulted in decreased oleic acid synthesis, lowered desaturation index profiles of the main polar lipids phosphatidylcholine and phosphatidylethanolamine, and decreased de novo synthesis of 14 C-labeled phospholipids, cholesterol and cholesterol esters, free fatty acids and triacylglycerols [114]. Interestingly, there was an inhibition in cellular proliferation and anchorage-independent growth in the SCD knockdown cells [114].…”