Inhibition of Stearoyl-CoA Desaturase 1 expression in human lung adenocarcinoma cells impairs tumorigenesis.
Saturated (SFA) and monounsaturated (MUFA) fatty acids, the most abundant fatty acid species, have many divergent biological effects including the regulation of cell proliferation, programmed cell death and lipid-mediated cytotoxicity. Their distribution is regulated by Stearoyl-CoA Desaturases (SCD), the enzymes that convert SFA into MUFA. A positive correlation between high levels of tissue MUFA and several types of cancer has been reported, but a causal relationship between the function of SCD1, the main human SCD isoform, and cancer development has not yet been firmly established. Here we report that the stable knockdown of SCD1 gene expression in A549 human lung adenocarcinoma cells decreased the ratio MUFA/SFA in total lipids and inhibited the incorporation of glucose into cell lipids. Cell proliferation and anchorage-independent growth were considerably decreased in SCD1-depleted cells, whereas the rate of apoptosis was elevated, with respect to control A549 cells. In addition, phosphorylation of Akt-Ser473 and GSK-3beta-Ser9 was found notably impaired in SCD1-ablated A549 cells. Interestingly, the effects of SCD1 blockade on Akt activation, cancer cell growth and apoptosis could not be reversed by exogenously added oleic acid. Remarkably, the reduction of SCD1 expression in lung cancer cells significantly delayed the formation of tumors and reduced the growth rate of tumor xenografts in mice. Our study demonstrates that SCD1 activity regulates Akt activation and determines the rate of cell proliferation, survival and invasiveness in A549 cancer cells and shows, for the first time, that SCD1 is a key factor in the regulation of tumorigenesis in vivo.
Scaglia
Natalia
N
Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, 1900 La Plata, Argentina.
Igal
R Ariel
RA
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D019301:Oleic Acid / Q000378:metabolism; D010641:Phenotype; D020033:Protein Isoforms; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
D008055:Lipids; D020033:Protein Isoforms; D019301:Oleic Acid; D013230:Stearoyl-CoA Desaturase; D051057:Proto-Oncogene Proteins c-akt