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J. Biol. Chem., Vol. 280, Issue 27, 25339-25349, July 8, 2005

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Stearoyl-CoA Desaturase Is Involved in the Control of Proliferation, Anchorage-independent Growth, and Survival in Human Transformed Cells^*

Natalia Scaglia and R. Ariel Igal¶

From the Instituto de Investigaciones Bioquímicas de La Plata, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 1900 La Plata, Argentina and the Department of Nutritional Sciences, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901

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.

Received for publication, February 1, 2005 , and in revised form, April 21, 2005.

^* This work was supported in part by grants from Fundación Antorchas (Grants 14068/28 to N. S. and 14022/60 to R. A. I.) and Agencia Nacional de Promoción Científica y Tecnológica (Grant 06-03823 to R. A. I.), Argentina. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Fig. S1.

^¶ A member of the Carrera del Investigador Científico (Scientific Research Career), Consejo Nacional de Investigaciones Científicas y Técnicas, Argentina. To whom correspondence should be addressed: Tel.: 54-221-482-4894; Fax: 54-221-4258-988; E-mail: aigal{at}atlas.med.unlp.edu.ar. or igal{at}aesop.rutgers.edu.

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