In vitro and in vivo study of epigallocatechin-3-gallate-induced apoptosis in aerobic glycolytic hepatocellular carcinoma cells involving inhibition of phosphofructokinase activity.
In vitro and in vivo study of epigallocatechin-3-gallate-induced apoptosis in aerobic glycolytic hepatocellular carcinoma cells involving inhibition of phosphofructokinase activity.
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DOI：
10.1038/srep28479
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发表时间：
2016-06-28
影响因子：
4.6
通讯作者：
Guo C
中科院分区：
文献类型：
--
作者：
Li S;Wu L;Feng J;Li J;Liu T;Zhang R;Xu S;Cheng K;Zhou Y;Zhou S;Kong R;Chen K;Wang F;Xia Y;Lu J;Zhou Y;Dai W;Guo C
糖酵解作为一种改变癌细胞的内在代谢，是癌症的一个重要标志。磷酸果糖激酶(PFK)是糖酵解途径中的代谢感受器，限制该酶的底物利用率作为化疗的靶点已被广泛研究。在本研究中，我们研究了绿茶的活性成分表没食子儿茶素没食子酸酯(EGCG)通过促进糖酵解肝细胞癌(HCC)细胞的糖酵解代谢而抑制细胞生长和诱导细胞凋亡的作用。EGCG调节PFK的寡聚体结构，可能导致代谢应激相关的细胞凋亡，并提示EGCG通过直接抑制PFK的活性而起作用。PFK活性抑制剂增强了这种作用，而变构激活剂则逆转了EGCG诱导的肝癌细胞死亡。该激活剂不能逆转PFK siRNA敲除诱导的细胞凋亡。EGCG增强了索拉非尼对有氧糖酵解肝癌细胞和异种移植小鼠模型中细胞生长的抑制作用。本研究提示EGCG在癌症治疗中具有潜在的辅助作用，值得在临床水平上进一步研究。
Glycolysis, as an altered cancer cell-intrinsic metabolism, is an essential hallmark of cancer. Phosphofructokinase (PFK) is a metabolic sensor in the glycolytic pathway, and restricting the substrate availability for this enzyme has been researched extensively as a target for chemotherapy. In the present study, we investigated that the effects of epigallocatechin-3-gallate (EGCG), an active component of green tea, on inhibiting cell growth and inducing apoptosis by promoting a metabolic shift away from glycolysis in aerobic glycolytic hepatocellular carcinoma (HCC) cells. EGCG modulated the oligomeric structure of PFK, potentially leading to metabolic stress associated apoptosis and suggesting that EGCG acts by directly suppressing PFK activity. A PFK activity inhibitor enhanced the effect, while the allosteric activator reversed EGCG-induced HCC cell death. PFK siRNA knockdown-induced apoptosis was not reversed by the activator. EGCG enhanced the effect of sorafenib on cell growth inhibition in both aerobic glycolytic HCC cells and in a xenograft mouse model. The present study suggests a potential role for EGCG as an adjuvant in cancer therapy, which merits further investigation at the clinical level.