Knowles Lynn M, Smith Jeffrey W
Cancer Research Center, Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
BMC Genomics. 2007 Jun 12;8:168. doi: 10.1186/1471-2164-8-168.
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. Inhibition of tumor FAS causes both cell cycle arrest and apoptosis, indicating FAS is a promising target for cancer treatment.
Here, 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 (> or = 1.5 fold) and 110 down-regulated genes (< or = 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.
Together 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.
脂肪生成酶脂肪酸合酶（FAS）在多种癌症中上调，因其增强肿瘤细胞存活的能力而被视为潜在的代谢致癌基因。抑制肿瘤FAS会导致细胞周期停滞和凋亡，表明FAS是癌症治疗的一个有前景的靶点。
在此，我们利用基因表达谱对MDA-MB-435乳腺癌细胞中siRNA介导的FAS敲低所影响的细胞过程进行了全面研究。该研究确定了169个上调基因（≥1.5倍）和110个下调基因（≤0.67倍）对FAS敲低的反应。这些基因调节肿瘤功能的几个方面，包括代谢、细胞存活/增殖、DNA复制/转录和蛋白质降解。使用基因集富集分析软件进行的定量通路分析进一步显示，FAS敲低的最显著影响是调节脂质代谢、糖酵解、三羧酸循环和氧化磷酸化的通路下调。这些变化与细胞周期停滞和死亡受体介导的凋亡通路中涉及的基因上调相关。
这些发现共同揭示了一个广泛的通路网络，该网络在对FAS敲低的反应中受到影响，并为这种酶在肿瘤细胞存活和增殖中的作用提供了新的见解。
