Zhan Yanai, Ginanni Nicole, Tota Michael R, Wu Margaret, Bays Nathan W, Richon Victoria M, Kohl Nancy E, Bachman Eric S, Strack Peter R, Krauss Stefan
Department of Cancer Biology and Therapeutics, Merck Research Laboratories, Boston, Massachusetts 02115, USA.
Clin Cancer Res. 2008 Sep 15;14(18):5735-42. doi: 10.1158/1078-0432.CCR-07-5074.
For many tumor cells, de novo lipogenesis is a requirement for growth and survival. A considerable body of work suggests that inhibition of this pathway may be a powerful approach to antineoplastic therapy. It has recently been shown that inhibition of various steps in the lipogenic pathway individually can induce apoptosis or loss of viability in tumor cells. However, it is not clear whether quantitative differences exist in the ability of lipogenic enzymes to control tumor cell survival. We present a systematic approach that allows for a direct comparison of the control of lipogenic pathway enzymes over tumor cell growth and apoptosis using different cancer cells.
RNA interference-mediated, graded down-regulation of fatty acid synthase (FAS) pathway enzymes was employed in combination with measurements of lipogenesis, apoptosis, and cell growth.
In applying RNA interference titrations to two lipogenic enzymes, acetyl-CoA carboxylase 1 (ACC1) and FAS, we show that ACC1 and FAS both significantly control cell growth and apoptosis in HCT-116 cells. These results also extend to PC-3 and A2780 cancer cells.
Control of tumor cell survival by different steps in de novo lipogenesis can be quantified. Because ACC1 and FAS both significantly control tumor cell growth and apoptosis, we propose that pharmacologic inhibitors of either enzyme might be useful agents in targeting cancer cells that critically rely on fatty acid synthesis. The experimental approach described here may be extended to other targets or disease-relevant pathways to identify steps suitable for therapeutic intervention.
对于许多肿瘤细胞而言，从头脂肪生成是其生长和存活所必需的。大量研究表明，抑制该途径可能是一种有效的抗肿瘤治疗方法。最近有研究显示，单独抑制脂肪生成途径中的各个步骤均可诱导肿瘤细胞凋亡或丧失活力。然而，脂肪生成酶在控制肿瘤细胞存活能力方面是否存在定量差异尚不清楚。我们提出了一种系统方法，可直接比较脂肪生成途径酶对不同癌细胞的肿瘤细胞生长和凋亡的控制作用。
采用RNA干扰介导的脂肪酸合酶（FAS）途径酶的分级下调，并结合脂肪生成、凋亡和细胞生长的测量。
在将RNA干扰滴定应用于两种脂肪生成酶，即乙酰辅酶A羧化酶1（ACC1）和FAS时，我们发现ACC1和FAS均能显著控制HCT-116细胞的细胞生长和凋亡。这些结果也适用于PC-3和A2780癌细胞。
从头脂肪生成中不同步骤对肿瘤细胞存活的控制作用可以进行量化。由于ACC1和FAS均能显著控制肿瘤细胞生长和凋亡，我们提出，这两种酶的药理抑制剂可能是针对严重依赖脂肪酸合成的癌细胞的有效药物。本文所述的实验方法可扩展至其他靶点或与疾病相关的途径，以确定适合治疗干预的步骤。
