PDF(Pubmed)
Abstract：
Since aerobic glycolysis was first observed in tumors almost a century ago by Otto Warburg, the field of cancer cell metabolism has sparked the interest of scientists around the world as it might offer new avenues of treatment for malignant cells. Our current study claims the discovery of gnetin H (GH) as a novel glycolysis inhibitor that can decrease metabolic activity and lactic acid synthesis and displays a strong cytostatic effect in melanoma and glioblastoma cells. Compared to most of the other glycolysis inhibitors used in combination with the complex-1 mitochondrial inhibitor phenformin (Phen), GH more potently inhibited cell growth. RNA-Seq with the T98G glioblastoma cell line treated with GH showed more than an 80-fold reduction in thioredoxin interacting protein (TXNIP) expression, indicating that GH has a direct effect on regulating a key gene involved in the homeostasis of cellular glucose. GH in combination with phenformin also substantially enhances the levels of p-AMPK, a marker of metabolic catastrophe. These findings suggest that the concurrent use of the glycolytic inhibitor GH with a complex-1 mitochondrial inhibitor could be used as a powerful tool for inducing metabolic catastrophe in cancer cells and reducing their growth.
摘要：
由于有氧糖酵解是近一个世纪前由奥托·沃堡首次在肿瘤中观察到的，癌细胞代谢领域引起了全世界科学家的兴趣，因为它可能为恶性细胞提供新的治疗途径。我们目前的研究声称发现gnetinH（GH）作为一种新型的糖酵解抑制剂，可以降低代谢活性和乳酸合成，并在黑色素瘤和胶质母细胞瘤细胞中表现出强烈的细胞抑制作用。与与复合物1线粒体抑制剂苯乙双胍（Phen）联合使用的大多数其他糖酵解抑制剂相比，GH更有效地抑制细胞生长。用GH处理的T98G胶质母细胞瘤细胞系的RNA-Seq显示硫氧还蛋白相互作用蛋白（TXNIP）表达减少了80倍以上，表明GH对调节参与细胞葡萄糖稳态的关键基因具有直接作用。GH与苯乙双胍组合也显著提高了P-AMPK的水平，代谢灾难的标志。这些发现表明，糖酵解抑制剂GH与复合物1线粒体抑制剂的同时使用可以用作诱导癌细胞代谢突变并减少其生长的强大工具。
