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Abstract
BackgroundThe lipogenic enzyme fatty acid synthase (FAS) is up-regulated in a wide variety of cancers, and is considered a potential metabolic oncogene by virtue of its ability to enhance tumor cell survival. Inhibition of tumor FAS causes both cell cycle arrest and apoptosis, indicating FAS is a promising target for cancer treatment.ResultsHere, we used gene expression profiling to conduct a global study of the cellular processes affected by siRNA mediated knockdown of FAS in MDA-MB-435 mammary carcinoma cells. The study identified 169 up-regulated genes (≥ 1.5 fold) and 110 down-regulated genes (≤ 0.67 fold) in response to knockdown of FAS. These genes regulate several aspects of tumor function, including metabolism, cell survival/proliferation, DNA replication/transcription, and protein degradation. Quantitative pathway analysis using Gene Set Enrichment Analysis software further revealed that the most pronounced effect of FAS knockdown was down-regulation in pathways that regulate lipid metabolism, glycolysis, the TCA cycle and oxidative phosphorylation. These changes were coupled with up-regulation in genes involved in cell cycle arrest and death receptor mediated apoptotic pathways.ConclusionTogether these findings reveal a wide network of pathways that are influenced in response to FAS knockdown and provide new insight into the role of this enzyme in tumor cell survival and proliferation.
Highlights
The lipogenic enzyme fatty acid synthase (FAS) is up-regulated in a wide variety of cancers, and is considered a potential metabolic oncogene by virtue of its ability to enhance tumor cell survival
Changes in gene expression resulting from knockdown of FAS MDA-MB-435 mammary carcinoma cells were selected as the model for defining the FAS knockdown signature
The non-silencing control small interfering RNA (siRNA) was selected based on minimal cross reactivity with known targets and had no impact on FAS expression or activity when compared against Lipofectamine 2000 transfection alone
Summary
The lipogenic enzyme fatty acid synthase (FAS) is up-regulated in a wide variety of cancers, and is considered a potential metabolic oncogene by virtue of its ability to enhance tumor cell survival. While normal cells obtain most fatty acids from circulating lipids, tumor cells have developed an increased reliance on endogenous fatty acid synthesis to satisfy their metabolic needs [2] This elevation of FAS occurs early in human cancer, is associated with aggressive forms of the disease, and is linked to poor prognosis [3,4,5,6,7]. The targeted knockdown of tumor FAS by small molecule inhibitors or small interfering RNA (siRNA) has been shown to induce both cell cycle arrest and apoptosis in cultured cells and suppresses tumor growth in xenograft bearing mice [813] This anti-tumor activity is linked to increased expres-
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