Low-dose arsenic induces chemotherapy protection via p53/NF-κB-mediated metabolic regulation.
Low-dose arsenic induces chemotherapy protection via p53/NF-κB-mediated metabolic regulation.
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作者：
大多数化疗药物主要通过诱导 DNA 损伤来杀死癌细胞，不幸的是，这也会对正常组织造成不良损伤，这主要是由于 p53 激活所致。我们报告了一种新的正常组织保护策略，涉及 p53/NF-κB 协调代谢调节。用低剂量砷预处理未转化细胞会诱导 p53 抑制和 NF-κB 激活，从而显着诱导糖酵解。值得注意的是，这种代谢转变为细胞提供了针对细胞毒性化疗的有效保护，将代谢途径与细胞抵抗结合起来。使用体外和体内模型，我们证明了砷介导的保护中功能性 p53 的绝对需要。一致的是，短暂的砷预处理仅选择性地保护正常组织，但不能保护肿瘤免受化疗的毒性。通过使用糖酵解抑制剂 2-脱氧葡萄糖，证明了糖酵解在保护正常组织中不可或缺的作用，该抑制剂几乎完全消除了低剂量砷介导的保护。总之，我们的工作表明，低剂量砷通过诱导糖酵解使正常细胞和组织对化疗引起的毒性产生抵抗力。
Most chemotherapeutical drugs kill cancer cells chiefly by inducing DNA damage, which unfortunately also causes undesirable injuries to normal tissues, mainly due to p53 activation. We report a novel strategy of normal tissue-protection that involves p53/NF-κB coordinated metabolic regulation. Pretreatment of untransformed cells with low doses of arsenic induced concerted p53 suppression and NF-κB activation, which elicited a marked induction of glycolysis. Significantly, this metabolic shift provided cells effective protection against cytotoxic chemotherapy, coupling the metabolic pathway to cellular resistance. Using both in vitro and in vivo models, we demonstrated an absolute requirement of functional p53 in arsenic-mediated protection. Consistently, a brief arsenic-pretreatment selectively protected only normal tissues but not tumors from toxicity of chemotherapy. An indispensable role of glycolysis in protecting normal tissues was demonstrated by using an inhibitor of glycolysis, 2-deoxyglucose, which almost totally abolished low-dose arsenic-mediated protection. Together, our work demonstrates that low-dose arsenic renders normal cells and tissues resistance to chemotherapy-induced toxicity by inducting glycolysis.
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影响因子：
4.8
作者：
Ak, Prashanth;Levine, Arnold J.
通讯作者：
Levine, Arnold J.
影响因子：
3.7
作者：
Hinkal G;Parikh N;Donehower LA
通讯作者：
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影响因子：
11.2
作者：
Huang Y;Zhang J;McHenry KT;Kim MM;Zeng W;Lopez-Pajares V;Dibble CC;Mizgerd JP;Yuan ZM
通讯作者：
Yuan ZM
DOI：
10.1097/01.jom.0000116801.67556.8f
发表时间：
2004-03-01
影响因子：
3.2
作者：
Lamm, SH;Engel, A;Wilson, R
通讯作者：
Wilson, R
影响因子：
10.4
作者：
Andrew AS;Warren AJ;Barchowsky A;Temple KA;Klei L;Soucy NV;O'Hara KA;Hamilton JW
通讯作者：
Hamilton JW