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首页> 外文期刊>International Journal of Molecular Sciences >Rapid Diminution in the Level and Activity of DNA-Dependent Protein Kinase in Cancer Cells by a Reactive Nitro-Benzoxadiazole Compound
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Rapid Diminution in the Level and Activity of DNA-Dependent Protein Kinase in Cancer Cells by a Reactive Nitro-Benzoxadiazole Compound

机译：反应性硝基苯并恶二唑化合物可快速减少癌细胞中DNA依赖性蛋白激酶的水平和活性

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摘要

The expression and activity of DNA-dependent protein kinase (DNA-PK) is related to DNA repair status in the response of cells to exogenous and endogenous factors. Recent studies indicate that Epidermal Growth Factor Receptor (EGFR) is involved in modulating DNA-PK. It has been shown that a compound 4-nitro-7-[(1-oxidopyridin-2-yl)sulfanyl]-2,1,3-benzoxadiazole (NSC), bearing a nitro-benzoxadiazole (NBD) scaffold, enhances tyrosine phosphorylation of EGFR and triggers downstream signaling pathways. Here, we studied the behavior of DNA-PK and other DNA repair proteins in prostate cancer cells exposed to compound NSC. We showed that both the expression and activity of DNA-PKcs (catalytic subunit of DNA-PK) rapidly decreased upon exposure of cells to the compound. The decline in DNA-PKcs was associated with enhanced protein ubiquitination, indicating the activation of cellular proteasome. However, pretreatment of cells with thioglycerol abolished the action of compound NSC and restored the level of DNA-PKcs. Moreover, the decreased level of DNA-PKcs was associated with the production of intracellular hydrogen peroxide by stable dimeric forms of Cu/Zn SOD1 induced by NSC. Our findings indicate that reactive oxygen species and electrophilic intermediates, generated and accumulated during the redox transformation of NBD compounds, are primarily responsible for the rapid modulation of DNA-PKcs functions in cancer cells.
机译：DNA依赖性蛋白激酶（DNA-PK）的表达和活性与细胞对外源性和内源性因子的反应中的DNA修复状态有关。最近的研究表明表皮生长因子受体（EGFR）参与调节DNA-PK。已显示带有硝基-苯并恶二唑（NBD）支架的化合物4-硝基-7-[（1-氧吡啶并-2-基）硫烷基] -2,1,3-苯并恶二唑（NSC）可增强酪氨酸磷酸化并触发下游信号通路。在这里，我们研究了暴露于化合物NSC的前列腺癌细胞中DNA-PK和其他DNA修复蛋白的行为。我们表明，细胞暴露于该化合物后，DNA-PKcs（DNA-PK的催化亚基）的表达和活性均迅速下降。 DNA-PKcs的下降与蛋白质泛素化增强有关，表明细胞蛋白酶体的活化。但是，用硫代甘油预处理细胞可消除化合物NSC的作用，并恢复DNA-PKcs的水平。此外，DNA-PKcs水平的降低与NSC诱导的稳定的二聚体形式的Cu / Zn SOD1产生胞内过氧化氢有关。我们的发现表明，在NBD化合物的氧化还原转化过程中产生和积累的活性氧和亲电子中间体，主要负责癌细胞中DNA-PKcs功能的快速调节。

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