De novo Lipogenesis Protects Cancer Cells from Free Radicals and Chemotherapeutics by Promoting Membrane Lipid Saturation
De novo Lipogenesis Protects Cancer Cells from Free Radicals and Chemotherapeutics by Promoting Membrane Lipid Saturation
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DOI：
10.1158/0008-5472.can-09-3871
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发表时间：
2010-10-15
期刊：
影响因子：
11.2
通讯作者：
Swinnen, Johannes V.
中科院分区：
文献类型：
--
作者：
Rysman, Evelien;Brusselmans, Koen;Swinnen, Johannes V.
癌细胞中从头脂肪生成的激活越来越被认为是侵袭性癌症的标志，并且已经涉及用于快速细胞增殖的膜的产生。在本报告中，我们提供的证据表明，这种激活具有更深远的作用。使用质谱为基础的磷脂分析方法，我们表明，临床肿瘤组织，显示脂肪生成表型的脂质饱和度的增加与nonlipogenic肿瘤相比。通过用脂肪生成抑制剂soraphen A治疗或通过用小干扰RNA靶向脂肪生成酶来抑制癌细胞中的脂肪生成开关，导致饱和和单不饱和磷脂物质的显著减少，并增加多不饱和的相对程度。由于多不饱和酰基链更容易过氧化，抑制脂肪生成增加了过氧化终产物的水平，使细胞更容易受到氧化应激诱导的细胞死亡。由于饱和脂质包装更密集，脂肪生成的调节也改变了横向和横向膜动力学，如膜靶向绿色荧光蛋白的扩散和对阿霉素的摄取和响应所揭示的。这些数据表明，从脂质摄取向从头脂肪生成转变脂质获取显著改变膜性质，并保护细胞免受内源性和外源性损伤。这些发现提供了重要的新的见解，从头脂肪生成在癌细胞中的作用，他们提供了一个合理的使用脂肪生成抑制剂作为抗肿瘤剂和化疗增敏剂。Cancer Res; 70（20）; 8117-26. (C)2010年AACR。
Activation of de novo lipogenesis in cancer cells is increasingly recognized as a hallmark of aggressive cancers and has been implicated in the production of membranes for rapid cell proliferation. In the current report, we provide evidence that this activation has a more profound role. Using a mass spectrometry-based phospholipid analysis approach, we show that clinical tumor tissues that display the lipogenic phenotype show an increase in the degree of lipid saturation compared with nonlipogenic tumors. Reversal of the lipogenic switch in cancer cells by treatment with the lipogenesis inhibitor soraphen A or by targeting lipogenic enzymes with small interfering RNA leads to a marked decrease in saturated and mono-unsaturated phospholipid species and increases the relative degree of polyunsaturation. Because polyunsaturated acyl chains are more susceptible to peroxidation, inhibition of lipogenesis increases the levels of peroxidation end products and renders cells more susceptible to oxidative stress-induced cell death. As saturated lipids pack more densely, modulation of lipogenesis also alters lateral and transversal membrane dynamics as revealed by diffusion of membrane-targeted green fluorescent protein and by the uptake and response to doxorubicin. These data show that shifting lipid acquisition from lipid uptake toward de novo lipogenesis dramatically changes membrane properties and protects cells from both endogenous and exogenous insults. These findings provide important new insights into the role of de novo lipogenesis in cancer cells, and they provide a rationale for the use of lipogenesis inhibitors as antineoplastic agents and as chemotherapeutic sensitizers. Cancer Res; 70(20); 8117-26. (C) 2010 AACR.