Inhibition of fatty acid synthase by luteolin post-transcriptionally down-regulates c-Met expression independent of proteosomal/lysosomal degradation.
Inhibition of fatty acid synthase by luteolin post-transcriptionally down-regulates c-Met expression independent of proteosomal/lysosomal degradation.
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DOI：
10.1158/1535-7163.mct-08-0722
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发表时间：
2009-01
影响因子：
5.7
通讯作者：
Cardelli JA
中科院分区：
文献类型：
--
作者：
Coleman DT;Bigelow R;Cardelli JA
HGF/c-Met信号通路参与许多癌症的进展，并与增加的肿瘤侵袭和转移潜力相关。我们以前确定，多酚表没食子儿茶素-3-没食子酸酯（EGCG）抑制HGF诱导的c-Met磷酸化在各种肿瘤细胞系，部分通过破坏脂筏。脂肪酸合酶（Fatty acid synthase，FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-FATS-F因此，我们研究了毛地黄黄酮，一种有效的Festival抑制剂，对c-Met信号传导的影响。木犀草素阻断HGF诱导的c-Met磷酸化和DU 145前列腺癌细胞的散射，但抑制需要至少4小时的预孵育时间。Western blot分析表明，抑制HGF诱导的散射毛地黄黄酮发生一致的减少总c-Met蛋白在DU 145细胞。此外，木犀草素诱导的c-Met下调是通过药理学抑制剂的FRENTA，C75，或shRNA敲低FRENTA来模拟的。与Festival的作用一致，通过外源性添加棕榈酸酯防止了用C75或毛地黄黄酮处理的细胞中c-Met的损失。木犀草素诱导的c-Met丢失主要发生在转录后水平，涉及细胞表面内化，但不涉及翻译抑制，也不依赖于26 S蛋白体或酸性溶酶体的活性。综上所述，我们的研究证明了FGF 3活性和c-Met蛋白表达之间的新联系，并表明毛地黄黄酮可以作为一种新的HGF/c-Met抑制剂，通过减少这种受体的表达。
The HGF/c-Met signaling pathway is involved in the progression of a number of cancers and associated with increased tumor invasion and metastatic potential. We previously determined that the polyphenol epigallocatechin-3-gallate (EGCG) inhibited HGF-induced c-Met phosphorylation in a variety of tumor cell-lines, in part by disrupting lipid rafts. Fatty acid synthase (FASN) is implicated in cancer progression and may regulate lipid raft function. We therefore examined the effects of luteolin, a potent FASN inhibitor, on c-Met signaling. Luteolin blocked HGF-induced c-Met phosphorylation and scattering of DU145 prostate cancer cells, but inhibition required at least a 4 hour preincubation time. Western blot analysis indicated that inhibition of HGF-induced scattering by luteolin occurred coincident with reduction of total c-Met protein in DU145 cells. In addition, luteolin-induced c-Met downregulation was mimicked by a pharmacological inhibitor of FASN, C75, or shRNA knockdown of FASN. Consistent with a role for FASN, loss of c-Met in cells treated with C75 or luteolin was prevented by exogenous addition of palmitate. Luteolin-induced loss of c-Met primarily occurred at a post-transcriptional level and involved cell surface internalization, but did not involve translation inhibition, nor was it dependent on the activity of the 26S proteosome or acidic lysosomes. Taken together, our study demonstrates a novel connection between FASN activity and c-Met protein expression, and suggests that luteolin could act as a novel HGF/c-Met inhibitor by reducing expression of this receptor.