A bioactive probe of the oxidative pentose phosphate cycle: novel strategy to reverse radioresistance in glucose deprived human colon cancer cells.
A bioactive probe of the oxidative pentose phosphate cycle: novel strategy to reverse radioresistance in glucose deprived human colon cancer cells.
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氧化戊糖磷酸循环的生物活性探针：逆转葡萄糖剥夺的人结肠癌细胞放射抗性的新策略。
DOI：
10.1016/j.tiv.2012.08.012
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Ayene,IraimoudiS
中科院分区：
文献类型：
--
作者：
Li,Jie;Ward,KathleenM;Zhang,Donglan;Dayanandam,Eswarkumar;Denittis,AlbertS;Prendergast,GeorgeC;Ayene,IraimoudiS
由于缺乏葡萄糖敏感的化学探针，葡萄糖剥夺对氧化戊糖磷酸循环（OPPC）功能，巯基稳态，蛋白质功能和细胞存活的具体影响仍不清楚。使用p53野生型和突变型人结肠细胞，我们确定了羟乙基二硫化物（HEDS）对NADPH，GSH，GSSG，总谷胱甘肽，总非蛋白和蛋白巯基水平，DNA修复蛋白Ku的功能，以及在正常葡萄糖或葡萄糖剥夺条件下对辐射诱导的自由基的敏感性的影响。HEDS在正常葡萄糖中快速解毒，但在葡萄糖耗尽状态下触发p53非依赖性代谢应激，导致NADPH、蛋白质和非蛋白质巯基稳态和Ku功能的丧失，并增强p53野生型和突变型细胞对辐射诱导的氧化应激的敏感性。此外，高浓度的HEDS单独诱导p53野生型细胞中的细胞死亡，而对p53突变细胞没有显著影响。HEDS提供了一个有用的工具，以深入了解葡萄糖代谢如何影响OPPC依赖性应激诱导的细胞功能和损伤，包括在肿瘤细胞中，我们的研究结果意味着一种新的治疗方法，以靶向葡萄糖剥夺肿瘤。我们的工作介绍了一种新的探针，以解决癌症代谢和缺血病理。
The specific effects of glucose deprivation on oxidative pentose phosphate cycle (OPPC) function, thiol homeostasis, protein function and cell survival remain unclear due to lack of a glucose-sensitive chemical probe. Using p53 wild type and mutant human colon cells, we determined the effects of hydroxyethyl disulfide (HEDS) on NADPH, GSH, GSSG, total glutathione, total non-protein and protein thiol levels, the function of the DNA repair protein Ku, and the susceptibility to radiation-induced free radicals under normal glucose or glucose-deprived conditions. HEDS is rapidly detoxified in normal glucose but triggered a p53-independent metabolic stress in glucose depleted state that caused loss of NADPH, protein and non-protein thiol homeostasis and Ku function, and enhanced sensitivity of both p53 wild type and mutant cells to radiation induced oxidative stress. Additionally, high concentration of HEDS alone induced cell death in p53 wild type cells without significant effect on p53 mutant cells. HEDS offers a useful tool to gain insights into how glucose metabolism affects OPPC dependent stress-induced cellular functions and injury, including in tumor cells, where our findings imply a novel therapeutic approach to target glucose deprived tumor. Our work introduces a novel probe to address cancer metabolism and ischemic pathology.