Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine.
Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine.
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发表时间：
1999-09
期刊：
影响因子：
11.2
通讯作者：
J. Sarkaria;Ericka C. Busby;R. Tibbetts;Pia Roos;Y. Taya;L. Karnitz;R. Abraham
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文献类型：
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作者：
J. Sarkaria;Ericka C. Busby;R. Tibbetts;Pia Roos;Y. Taya;L. Karnitz;R. Abraham
咖啡因暴露使肿瘤细胞对电离辐射和其他基因毒性物质敏感。咖啡因的辐射致敏效应与多个DNA损伤反应细胞周期检查点的破坏有关。这些检查点缺陷与共济失调毛细血管扩张（A-T）相似，表明咖啡因可能抑制dna受损细胞中A-T突变（ATM）依赖性检查点途径中的一种或多种成分。我们现在表明，咖啡因在与诱导放射致敏相似的药物浓度下抑制ATM和相关激酶，ATM和rad3相关（ATR）的催化活性。此外，与atm缺陷细胞一样，在G2期照射的经咖啡因处理的A549肺癌细胞不能阻止有丝分裂的进展，并且s期照射的细胞表现出耐辐射DNA合成。同样浓度的咖啡因也能抑制γ和UV辐射诱导的p53 Ser15的磷酸化，这种修饰可能是由ATM和ATR激酶直接介导的。DNA依赖性蛋白激酶是另一种参与DNA损伤修复的与atm相关的蛋白质，它对咖啡因的抑制作用有抵抗力。同样，G2检查点激酶hChk1的催化活性仅被咖啡因轻微抑制，但被结构独特的放射增敏剂UCN-01有效抑制。这些数据表明，咖啡因的放射增敏作用与抑制ATM和ATR蛋白激酶活性有关，这两种蛋白都是开发新型抗癌药物的相关靶点。
Caffeine exposure sensitizes tumor cells to ionizing radiation and other genotoxic agents. The radiosensitizing effects of caffeine are associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints. The similarity of these checkpoint defects to those seen in ataxia-telangiectasia (A-T) suggested that caffeine might inhibit one or more components in an A-T mutated (ATM)-dependent checkpoint pathway in DNA-damaged cells. We now show that caffeine inhibits the catalytic activity of both ATM and the related kinase, ATM and Rad3-related (ATR), at drug concentrations similar to those that induce radiosensitization. Moreover, like ATM-deficient cells, caffeine-treated A549 lung carcinoma cells irradiated in G2 fail to arrest progression into mitosis, and S-phase-irradiated cells exhibit radioresistant DNA synthesis. Similar concentrations of caffeine also inhibit gamma- and UV radiation-induced phosphorylation of p53 on Ser15, a modification that may be directly mediated by the ATM and ATR kinases. DNA-dependent protein kinase, another ATM-related protein involved in DNA damage repair, was resistant to the inhibitory effects of caffeine. Likewise, the catalytic activity of the G2 checkpoint kinase, hChk1, was only marginally suppressed by caffeine but was inhibited potently by the structurally distinct radiosensitizer, UCN-01. These data suggest that the radiosensitizing effects of caffeine are related to inhibition of the protein kinase activities of ATM and ATR and that both proteins are relevant targets for the development of novel anticancer agents.