Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells
Inhibition of fatty acid synthase (FAS) suppresses HER2/neu (erbB-2) oncogene overexpression in cancer cells
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DOI：
10.1073/pnas.0403390101
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发表时间：
2004-07-20
影响因子：
11.1
通讯作者：
Lupu, R
中科院分区：
文献类型：
--
作者：
Menendez, JA;Vellon, L;Lupu, R
脂肪酸合成酶(Fas)活性是治疗癌症和肥胖的潜在靶点。在这里，我们已经确定了Fas和HER2(erb B-2)癌基因之间的分子联系，这是一个预后不良的标志，在30%的乳腺癌和卵巢癌中过度表达。药理Fas抑制剂蓝蛋白和C75被发现抑制乳腺和卵巢HER2过表达的p185(HER2)癌蛋白表达和酪氨酸激酶活性。同样，当利用高度序列特异性的RNA干扰(RNAi)机制沉默Fas基因表达时，p185(HER2)的表达显著下调。药理学和RNAi介导的Fas沉默特异性地下调了HER2的mRNA，同时导致了HER2的转录抑制因子PEA3的显著上调。P185(HER2)的胞质重分布与Fas RNAi转染细胞的明显形态变化有关，而Fas的化学抑制剂促进了p185(HER2)的显著核积聚。化学Fas抑制剂和针对p185(HER2)曲妥珠单抗的人源化抗体同时靶向Fas和HER2，对HER2过表达具有协同的细胞毒作用。类似地，同时RNAi介导的Fas和HER2基因的沉默协同刺激了HER2过表达的细胞的凋亡。药物抑制剂或小干扰RNA同时抑制Fas和HER2后，p185(HER2)的表达协同下调。这些发现提供了Fas通过特异性调控与恶性转化密切相关的致癌蛋白而在癌症进化中发挥积极作用的证据，有力地表明HER2癌基因可能是肿瘤相关Fas过度活动扰乱后能量失衡的关键分子传感器。
Fatty acid synthase (FAS) activity is a potential therapeutic target to treat cancer and obesity. Here, we have identified a molecular link between FAS and HER2 (erbB-2) oncogene, a marker for poor prognosis that is overexpressed in 30% of breast and ovarian cancers. Pharmacological FAS inhibitors cerulenin and C75 were found to suppress p185(HER2) oncoprotein expression and tyrosine-kinase activity in breast and ovarian HER2 overexpressors. Similarly, p185(HER2) expression was dramatically down-regulated when FAS gene expression was silenced by using the highly sequence-specific mechanism of RNA interference (RNAi). Pharmacological and RNAi-mediated silencing of FAS specifically down-regulated HER2 mRNA and, concomitantly, caused a prominent up-regulation of PEA3, a transcriptional repressor of HER2. A cytoplasmic redistribution of p185(HER2) was associated with marked morphological changes of FAS RNAi-transfected cells, whereas chemical inhibitors of FAS promoted a striking nuclear accumulation of p185(HER2). The simultaneous targeting of FAS and HER2 by chemical FAS inhibitors and the humanized antibody directed against p185(HER2) trastuzumab, respectively, was synergistically cytotoxic toward HER2 overexpressors. Similarly, concurrent RNAi-mediated silencing of FAS and HER2 genes synergistically stimulated apoptotic cell death in HER2 overexpressors. p185(HER2) was synergistically down-regulated after simultaneous inhibition of FAS and HER2 by either pharmacological inhibitors or small interfering RNA. These findings provide evidence of an active role of FAS in cancer evolution by specifically regulating oncogenic proteins closely related to malignant transformation, strongly suggesting that HER2 oncogene may act as the key molecular sensor of energy imbalance after the perturbation of tumor-associated FAS hyperactivity in cancer cells.