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首页> 外文OA文献 >Role of APE1 in differentiated neuroblastoma SH-SY5Y cells in response to oxidative stress; Use of APE1 small molecule inhibitors to delineate APE1 functions
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Role of APE1 in differentiated neuroblastoma SH-SY5Y cells in response to oxidative stress; Use of APE1 small molecule inhibitors to delineate APE1 functions

机译：APE1在分化成神经母细胞瘤SH-SY5Y细胞对氧化应激反应中的作用；使用APE1小分子抑制剂描绘APE1功能

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Oxidative DNA damage has been implicated in a number of central nervous system pathologies. The base excision repair (BER) pathway is one of the most important cellular protection mechanisms that respond to oxidative DNA damage. Human apurinic (apyrimidinic) endonuclease/redox effector factor (APE1/Ref-1 or APE1) is an essential enzyme in the BER pathway and is expressed in both mitotic and post-mitotic cells in humans. In neurons, a reduction of APE1 expression increases chemotherapy-induced cytotoxicity, while overexpression of APE1 protects cells against the cytotoxicity. However, given the multiple functions of APE1, knockdown of total APE1 is not completely informative of whether it is the redox or DNA repair activity, or interactions with other proteins. Therefore, the use of selective small molecules that can block each function independent of the other is of great benefit in ascertaining APE1 function in post-mitotic cells. In this study, we chose differentiated SH-SY5Y cells as our post-mitotic cell line model to investigate whether a drug-induced decrease in APE1 DNA repair or redox activity contributes to the growth and survival of post-mitotic cells under oxidative DNA damaging conditions. Here, we demonstrate that overexpression of WT-APE1 or C65-APE1 (repair competent) results in significant increase in cell viability after exposure to H2O2. However, the 177/226-APE1 (repair deficient) did not show a protective effect. This phenomenon was further confirmed by the use of methoxyamine (MX), which blocks the repair activity of APE1 that results in enhanced cell killing and apoptosis in differentiated SH-SY5Y cells and in neuronal cultures after oxidative DNA damaging treatments. Blocking APE1 redox function by a small molecule inhibitor, BQP did not decrease viability of SH-SY5Y cells or neuronal cultures following oxidative DNA damaging treatments. Our results demonstrate that the DNA repair function of APE1 contributes to the survival of nondividing post-mitotic cells following oxidative DNA damage.
机译：氧化性DNA损伤与许多中枢神经系统疾病有关。碱基切除修复（BER）途径是对氧化DNA损伤做出反应的最重要的细胞保护机制之一。人嘌呤（apyrimidinic）核酸内切酶/氧化还原效应因子（APE1 / Ref-1或APE1）是BER途径中必不可少的酶，在人的有丝分裂和有丝分裂后细胞中均表达。在神经元中，APE1表达的减少会增加化疗诱导的细胞毒性，而APE1的过表达保护细胞免受细胞毒性的影响。但是，鉴于APE1的多种功能，敲除总APE1并不能完全说明其是氧化还原或DNA修复活性，还是与其他蛋白质的相互作用。因此，使用选择性小分子可以阻断彼此独立的功能，对确定有丝分裂后细胞中APE1的功能非常有用。在这项研究中，我们选择分化的SH-SY5Y细胞作为有丝分裂后细胞系模型，以研究药物诱导的APE1 DNA修复或氧化还原活性降低是否在氧化性DNA损伤条件下促进有丝分裂后细胞的生长和存活。 。在这里，我们证明了WT-APE1或C65-APE1（修复能力）的过表达导致暴露于H2O2后细胞活力的显着增加。但是，177 / 226-APE1（修复缺陷）没有显示保护作用。通过使用甲氧基胺（MX）进一步证实了这一现象，该甲氧基胺可阻断APE1的修复活性，从而导致分化的SH-SY5Y细胞和氧化性DNA损伤处理后神经元培养物中细胞的杀伤和凋亡增强。 BQP通过小分子抑制剂阻断APE1的氧化还原功能，并没有降低SH-SY5Y细胞或神经元培养物在氧化性DNA损伤处理后的活力。我们的结果表明，APE1的DNA修复功能有助于氧化性DNA损伤后有分裂的有丝分裂后细胞的存活。

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