Fatty acid metabolism in breast cancer cells:: differential inhibitory effects of epigallocatechin gallate (EGCG) and C75
Fatty acid metabolism in breast cancer cells:: differential inhibitory effects of epigallocatechin gallate (EGCG) and C75
复制标题
DOI：
10.1007/s10549-007-9678-5
复制
发表时间：
2008-06-01
影响因子：
3.8
通讯作者：
Colomer, Ramon
中科院分区：
文献类型：
--
作者：
Puig, Teresa;Vazquez-Martin, Alejandro;Colomer, Ramon
内源性脂肪酸代谢是维持癌细胞恶性表型的关键。脂肪生成由脂肪酸合成酶（FATCH）调节;脂肪酸分解由肉毒碱棕榈酰转移酶-1（CPT-I）调节。在乳腺癌和大多数常见的人类癌中，FXR高表达。几种化合物可以抑制Festival，尽管这种抑制的特异性程度尚未得到解决。我们测试了C75和（-）-表没食子儿茶素-3-没食子酸酯（EGCG）对人乳腺癌细胞中脂肪酸代谢途径、细胞增殖、诱导凋亡和细胞信号传导的影响。我们的研究结果表明，C75和EGCG在阻断Festival活性方面具有相当的效果。用EGCG或C75处理癌细胞诱导凋亡，并导致癌蛋白HER 2、AKT和ERK 1/2的活性形式以类似程度减少。相反，我们观察到C75和表没食子儿茶素没食子酸酯（EGCG）对脂肪酸氧化途径的显著差异效应。虽然EGCG对CPT-1活性没有影响或中度降低，但C75刺激CPT-1活性（高达129%），即使在抑制水平的丙二酰辅酶A（CPT-1酶的有效抑制剂）存在下也是如此。综上所述，这些发现表明，Festival的药理学抑制与CPT-1与EGCG而不是C75的刺激解偶联，表明EGCG可能不含与C75相关的CPT-1相关的体内体重减轻。我们的研究结果确立了表没食子儿茶素没食子酸酯作为一种有效的和特异性的脂肪酸合成抑制剂（FATCH），这可能有望成为一种靶向抗癌药物。
Endogenous fatty acid metabolism is crucial to maintain the cancer cell malignant phenotype. Lipogenesis is regulated by the enzyme fatty acid synthase (FASN); and breakdown of fatty acids is regulated by carnitine palmitoyltransferase-1 (CPT-I). FASN is highly expressed in breast cancer and most common human carcinomas. Several compounds can inhibit FASN, although the degree of specificity of this inhibition has not been addressed. We have tested the effects of C75 and (-)-epigallocatechin-3-gallate (EGCG) on fatty acid metabolism pathways, cellular proliferation, induction of apoptosis and cell signalling in human breast cancer cells. Our results show that C75 and EGCG had comparable effects in blocking FASN activity. Treating cancer cells with EGCG or C75 induced apoptosis and caused a decrease in the active forms of oncoprotein HER2, AKT and ERK1/2 to a similar degree. We observed, in contrast, marked differential effects between C75 and EGCG on the fatty acid oxidation pathway. While EGCG had either no effect or a moderate reduction in CPT-I activity, C75 stimulated CPT-I activity (up to 129%), even in presence of inhibitory levels of malonyl-CoA, a potent inhibitor of the CPT-I enzyme. Taken together, these findings indicate that pharmacological inhibition of FASN occurs uncoupled from the stimulation of CPT-I with EGCG but not with C75, suggesting that EGCG might be free of the CPT-I related in vivo weight-loss that has been associated with C75. Our results establish EGCG as a potent and specific inhibitor of fatty acid synthesis (FASN), which may hold promise as a target-directed anti-cancer drug.