Why does tumor-associated fatty acid synthase (oncogenic antigen-519) ignore dietary fatty acids?
Why does tumor-associated fatty acid synthase (oncogenic antigen-519) ignore dietary fatty acids?
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DOI：
10.1016/j.mehy.2004.07.022
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发表时间：
2005-01-01
影响因子：
4.7
通讯作者：
Lupu, R
中科院分区：
文献类型：
--
作者：
Menendez, JA;Colomer, R;Lupu, R
在人类恶性肿瘤的群体研究中，脂肪酸合成酶（FAS）催化的脂肪酸从头生物合成的超活化是与肿瘤毒力相关的分子标志物。这种激活似乎与肿瘤转化有关，因为在癌前病变中也发现了高水平的FAS。癌症对加速脂肪生成的依赖性不同于正常人体组织，其中FAS被饮食中少量脂肪酸的存在抑制。癌细胞组成性地表现出FAS过度表达和过度活跃的分子机制已经开始出现。最近在几种癌细胞模型中证实了促分裂原活化蛋白激酶（MAPK）细胞外信号调节激酶（MAPK ERK 1/2）和磷脂酰肌醇-3 '-激酶（PI-3' K）/蛋白激酶B（AKT）转导级联在FAS过表达中的积极参与。引人注目的是，胰岛素调节的脂肪细胞中FAS表达的刺激也由PI-3 ′ K途径介导，其中AKT作为下游效应物参与。此外，已证明肿瘤细胞中的FAS过表达是通过修饰转录因子固醇调节元件结合蛋白-1c：（SREBP-1c）而发生的，SREBP-1c是肝脏和脂肪组织中FAS的主要调节因子，而这反过来又是已知的。受到MAPK ERK 1/2和PI-3 'K/AKT途径的调节。因此，在正常细胞和癌细胞中调节FAS表达的信号转导途径似乎共享几个下游元件。然而，控制癌细胞中FAS表达的上游机制必须不同于正常组织中的机制，因为肿瘤相关的FAS表达似乎对营养信号不敏感。在癌前病变中，我们假设癌前细胞中FAS的早期激活代表了一种生存策略，其发生是为了补偿氧和膳食脂肪酸的不足，缺乏血管生成。因此，FAS活化反映了脂肪生成途径的表观遗传失调，以响应含有氧合不良区域的肿瘤微环境。在这种不寻常的代谢情况下，FAS上调也代表了在不存在外源性膳食脂肪酸的情况下维持存活细胞的高增殖率的代谢策略。同时，各种致癌变化（H-ras、erB B-2等）可能导致MAPK和PI-3 ′ K/AKT信号级联的组成性激活，这反过来又可以激活SREBP-1c，并随后激活肿瘤相关FAS催化的内源性脂肪生成。此后，高水平的FAS维持与响应于癌症相关的生长因子（例如，EGF、调蛋白）和/或生长因子受体（例如，EGFR，Her-2/neu）。由这些致癌变化驱动的异常MAPK和PI-3 ′ K/AKT级联破坏了饮食脂肪酸生理浓度的下调作用，导致癌症相关FAS对营养信号不敏感。该模型并不排除FAS基因对正常脂肪酸下调作用的应答能力的根本差异也可能与致癌信号协同相互作用，从而在癌细胞中组成性地维持升高的FAS依赖性从头内源性脂肪酸生物合成，尽管循环膳食脂肪酸水平高。(C)2004爱思唯尔有限公司保留所有权利。
The hyperactivation of fatty acid synthase (FAS)-catalyzed de novo biosynthesis of fatty acids is a molecular marker linked to tumor virulence in population studies of human malignancies. This activation appears to be linked to neoplastic transformation, since high levels of FAS have also been identified in pre-malignant lesions. This dependence of cancer upon accelerated lipogenesis differs from normal human tissues, in which FAS is suppressed by the presence of small amounts of fatty acids in the diet. The molecular mechanisms by which cancer cells constitutively exhibit FAS overexpression and hyperactivity have begun to emerge. The active involvement of the mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (MAPK ERK1/2) and phosphatidylinositol-3'-kinase (PI-3'K)/protein kinase B (AKT) transduction cascades in the overexpression of FAS has been recently demonstrated in several cancer cell models. Strikingly, insulin-regulated stimulation of FAS expression in adipose cells is also mediated by the PI-3'K pathway with AKT being involved as a downstream effector. Moreover, FAS overexpression in tumor cells has been demonstrated to occur through a modification of the transcription factor sterol regulatory element-binding protein-1c: (SREBP-1c), the major regulatory factor of FAS in Liver and adipose tissues, which, in turn, is known to be regulated by MAPK ERK1/2 and PI-3'K/AKT pathways. Therefore, the signal transduction pathways regulating FAS expression in normal and cancer cells seem to share several downstream elements. However, the upstream mechanisms controlling FAS expression in cancer cells must be different from those in normal tissues, since tumor-associated FAS expression seems to be insensitive to nutritional signals. In pre-neoplastic lesions, we hypothesize that the early activation of FAS in premalignant cells represents a survival strategy which occurs to compensate for an insufficiency of both oxygen and dietary fatty acids due to, e.g., lack of angiogenesis. Thus, FAS activation reflects an epigenetic dysregulation of the lipogenic pathway in response to the microenvironment of tumors containing regions of poor oxygenation. Upon this unusual metabolic situation, FAS up-regulation also represent a metabolic strategy to maintain high proliferation rates of surviving cells in the absence of exogenous dietary fatty acids. Concomitantly, a variety of oncogenic changes (H-ras, erb B-2, etc.) may result in the constitutive activation of MAPK and PI-3'K/AKT signaling cascades, which, in turn, can activate SREBP-1c: and, subsequently, tumor-associated FAS-catalyzed endogenous lipogenesis. Thereafter, high levels of FAS are maintained in coordination with increased demand for fatty acid metabolism and/or membrane synthesis in response to cancer-related overexpression of growth factors (e.g., EGF, heregulin) and/or growth factor receptors (e.g., EGFR, Her-2/neu). The aberrant MAPK and PI-3'K/AKT cascades driven by these oncogenic changes subvert the downregulatory effects of physiological concentrations of dietary fatty acids, resulting in a cancer-associated FAS insensitivity to nutritional signals. This model does not exclude that fundamental differences in the ability of FAS gene to respond to normal fatty acid's downregulatory actions may also synergistically interact with oncogenic signals to constitutively maintain an elevated FAS-dependent de novo endogenous fatty acid biogenesis in cancer cells in spite of high levels of circulating dietary fatty acids. (C) 2004 Elsevier Ltd. All rights reserved.