A fatty acid synthase blockade induces tumor cell-cycle arrest by down-regulating Skp2
A fatty acid synthase blockade induces tumor cell-cycle arrest by down-regulating Skp2
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DOI：
10.1074/jbc.m405061200
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发表时间：
2004-07-16
影响因子：
4.8
通讯作者：
Smith, JW
中科院分区：
文献类型：
--
作者：
Knowles, LM;Axelrod, F;Smith, JW
在真核生物中，脂肪酸合酶 (FAS) 是负责合成棕榈酸酯的酶，棕榈酸酯是长链非必需脂肪酸的前体。 FAS 在多种癌症中表达上调，并已被建议作为相关的药物靶点。在这里，采用两种独立的方法来敲除 FAS，然后探讨其与肿瘤细胞增殖的联系。在一种方法中，奥利司他（一种被批准用于治疗肥胖症的药物）被用作 FAS 硫酯酶功能的有效抑制剂。在一个单独的策略中，FAS 的表达通过小干扰 RNA 的靶向敲除来抑制。在这两种情况下，FAS 活性的消除都会导致 Skp2 的急剧下调，Skp2 是 E3 泛素连接酶的一个组成部分，控制着 p27(Kip1) 的更新。这些效应最终与视网膜母细胞瘤蛋白途径相关，并导致细胞周期停滞在 G(1)/S 边界。总而言之，该研究的结果揭示了脂肪酸合酶和细胞周期调节蛋白的泛素依赖性蛋白水解之间未被认识到的联系。
In eukaryotes, fatty acid synthase (FAS) is the enzyme responsible for synthesis of palmitate, the precursor of long-chain nonessential fatty acids. FAS is up-regulated in a wide range of cancers and has been suggested as a relevant drug target. Here, two independent approaches are taken toward knocking down FAS and then probing its connection to tumor cell proliferation. In one approach, Orlistat, a drug approved for treating obesity, is used as a potent inhibitor of the thioesterase function of FAS. In a separate strategy, the expression of FAS is suppressed by targeted knock-down with small interfering RNA. In both circumstances, the ablation of FAS activity causes a dramatic down-regulation of Skp2, a component of the E3 ubiquitin ligase that controls the turnover of p27(Kip1). These effects ultimately tie into the retinoblastoma protein pathway and lead to a cell-cycle arrest at the G(1)/S boundary. Altogether, the findings of the study reveal unappreciated links between fatty acid synthase and ubiquitin-dependent proteolysis of cell-cycle regulatory proteins.