Inhibition of Stearoyl-CoA Desaturase 1 expression in human lung adenocarcinoma cells alters signaling pathways and impairs tumorigenesis

N. SCAGLIA; R. A. IGAL

Congreso; Gordon Research Conferences. Molecular & Cellular Biology of Lipids; 2007

Saturated (SFA) and monounsaturated (MUFA) fatty acids, the most abundant fatty acid species, have many divergent biological effects including 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 decreases the ratio SFA/MUFA in total lipids, with reduced incorporation of SFA into phospholipids but increased SFA acylation into triacylglycerol. Cell proliferation and anchorage-independent growth were considerably reduced in SCD1-depleted cells, whereas the rate of apoptosis was elevated, with respect to control A549 cells. Interestingly, these effects could not be reversed by exogenously added oleic acid. In addition, we studied whether SCD1 expression levels affects the activity of signaling networks related to cell proliferation, apoptosis and neoplastic transformation in human cells, such as Akt, and PKC. We observed that phosphorylation of Akt-Ser473 and GSK-3b was found notably decreased in SCD1-ablated cells, suggesting that SCD1 may regulate cell growth and survival in cancer cells by modulating the Akt signaling pathway. 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 suggests that SCD1 activity regulates the levels of proliferative signaling proteins and determines the rate of cell proliferation, survival and invasiveness in lung cancer cells. Also, we report, for the first time, that SCD1 is a key factor in the regulation of tumorigenesis in vivo.