Laboratory for Experimental Medicine and Endocrinology, K.U. Leuven, Leuven, Belgium.
Cancer Res. 2010 Oct 15;70(20):8117-26. doi: 10.1158/0008-5472.CAN-09-3871. Epub 2010 Sep 28.
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.
越来越多的证据表明，癌细胞中从头合成脂肪的激活是侵袭性癌症的一个标志，并与快速增殖细胞的膜生成有关。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。使用基于质谱的磷脂分析方法，我们发现显示脂肪生成表型的临床肿瘤组织与非脂肪生成肿瘤相比，脂质饱和度增加。用脂肪生成抑制剂 soraphen A 处理或用小干扰 RNA 靶向脂肪生成酶使癌细胞中的脂肪生成开关逆转，会导致饱和和单不饱和磷脂种类的显著减少，并增加多不饱和的相对程度。因为多不饱和酰基链更容易发生过氧化，脂肪生成的抑制会增加过氧化终产物的水平，并使细胞更容易受到氧化应激诱导的细胞死亡。由于饱和脂质堆积更紧密，脂肪生成的调节也会改变侧向和横向膜动力学，如膜靶向绿色荧光蛋白的扩散以及对阿霉素的摄取和反应所揭示的那样。这些数据表明，将脂质获取从脂质摄取转移到从头合成脂肪会显著改变膜性质，并使细胞免受内源性和外源性损伤。这些发现为从头合成脂肪在癌细胞中的作用提供了重要的新见解，并为使用脂肪生成抑制剂作为抗肿瘤剂和化疗增敏剂提供了依据。
