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 ceramide-independent manner. Finally, stearoyl-CoA desaturase-deficient cells were more sensitive to palmitic acid-induced 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.
Highlights
Saturated (SFA)1 and monounsaturated (MUFA) fatty acids are the most abundant fatty acids present in mammalian organisms
The different grade of stearoyl-CoA desaturase (SCD) deficiency in independent hSCDas clones was mirrored by a proportionate decay in MUFA levels, indicating that SCD is the main regulator of MUFA content in SV40-transformed cells
In addition to the profound alterations in fatty acid distribution in the main phospholipid fractions promoted by SCD knockdown, the overall synthesis of phospholipids was significantly reduced in the SCD-deficient cell lines
Summary
Synthesis of phospholipids and cholesterol, supporting the idea that MUFA synthesis is an integral part of the program of membrane synthesis. We designed a model of reduced SCD gene expression in human cells To this end, we employed SV40-transformed human lung fibroblasts, because this cell line bears several biological and biochemical features that make these cells an advantageous model to test the effects of SCD deficiency in lipid homeostasis as well as in cell proliferation, carcinogenesis, and programmed cell death as follows: (i) SCD protein and activity levels are significantly up-regulated by SV40-transformation, leading to a high MUFA synthesis and content [15]; (ii) As a human cell strain, SV40-WI38 cells contains the main SCD isoenzyme present in human cells, if not the only active isoform [5, 6, 17], which may increase the understanding of SCD functions in cell physiology; (iii) these human cells possess the advantage of a well known mechanism for transformation based on the inactivation of p53 and Rb activities, a condition that is present in the most frequent human cancers [18, 19]. We take this to suggest that SCD action is important in the physiology of proliferating cells, even in conditions of normal supply of MUFA
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