Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia.
Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia.
复制标题
DOI：
10.1158/0008-5472.613.65.2
复制
发表时间：
2005-01
期刊：
影响因子：
11.2
通讯作者：
R. Xu;H. Pelicano;Yan Zhou;J. Carew;Li Feng;K. Bhalla;M. Keating;Peng Huang
中科院分区：
文献类型：
--
作者：
R. Xu;H. Pelicano;Yan Zhou;J. Carew;Li Feng;K. Bhalla;M. Keating;Peng Huang
癌细胞通常表现出增加的用于ATP生成的糖酵解（瓦尔堡效应），部分原因是线粒体呼吸损伤和缺氧，这通常与对治疗剂的抗性有关。在这里，我们报道了糖酵解的抑制严重消耗癌细胞中的ATP，特别是在具有线粒体呼吸缺陷的癌细胞克隆中，并导致糖酵解-凋亡整合分子BAD在Ser（112）处的快速去磷酸化，BAX重新定位于线粒体，以及大量细胞死亡。重要的是，糖酵解的抑制在低氧环境中有效地杀死结肠癌细胞和淋巴瘤细胞，其中癌细胞表现出高糖酵解活性和对常见抗癌剂的敏感性降低。糖酵解抑制ATP的消耗也有效地诱导多药耐药细胞的凋亡，这表明剥夺细胞能量供应可能是克服多药耐药的有效途径。我们的研究显示了一种有希望的治疗策略，可以有效地杀死癌细胞并克服耐药性。由于瓦尔堡效应和缺氧在人类癌症中常见，这些发现可能具有广泛的临床意义。
Cancer cells generally exhibit increased glycolysis for ATP generation (the Warburg effect) due in part to mitochondrial respiration injury and hypoxia, which are frequently associated with resistance to therapeutic agents. Here, we report that inhibition of glycolysis severely depletes ATP in cancer cells, especially in clones of cancer cells with mitochondrial respiration defects, and leads to rapid dephosphorylation of the glycolysis-apoptosis integrating molecule BAD at Ser(112), relocalization of BAX to mitochondria, and massive cell death. Importantly, inhibition of glycolysis effectively kills colon cancer cells and lymphoma cells in a hypoxic environment in which the cancer cells exhibit high glycolytic activity and decreased sensitivity to common anticancer agents. Depletion of ATP by glycolytic inhibition also potently induced apoptosis in multidrug-resistant cells, suggesting that deprivation of cellular energy supply may be an effective way to overcome multidrug resistance. Our study shows a promising therapeutic strategy to effectively kill cancer cells and overcome drug resistance. Because the Warburg effect and hypoxia are frequently seen in human cancers, these findings may have broad clinical implications.