Specific inhibition of the redox activity of ape1/ref-1 by e3330 blocks tnf-α-induced activation of IL-8 production in liver cancer cell lines.
Specific inhibition of the redox activity of ape1/ref-1 by e3330 blocks tnf-α-induced activation of IL-8 production in liver cancer cell lines.
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DOI：
10.1371/journal.pone.0070909
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Tell G
中科院分区：
文献类型：
--
作者：
Cesaratto L;Codarin E;Vascotto C;Leonardi A;Kelley MR;Tiribelli C;Tell G
APE1/Ref-1通过dna修复功能和NF-κB转录因子的共激活活性，是细胞对氧化应激反应的主要调节因子。APE1在通过调节细胞因子表达来控制氧化应激炎症过程中起着核心作用，其过表达是包括肝癌在内的不同肿瘤发生化疗耐药的原因。我们研究了在脂肪酸积累相关的肝细胞损伤过程中APE1过表达的功能作用，以及APE1在炎症过程中的氧化还原功能。用功能性和非功能性APE1编码质粒稳定转染HepG2细胞，检测APE1过表达对基因毒性化合物或FAs积累的保护作用。在APE1氧化还原抑制剂E3330存在或不存在的情况下，TNF-α刺激JHH6细胞。采用荧光素酶报告基因法检测IL-8启动子活性，Real-Time PCR检测基因表达，ELISA检测细胞因子（IL-6、IL-8、IL-12）水平。过表达APE1不能阻止脂质积累引起的细胞毒性。E3330处理通过改变APE1亚细胞运输阻止NF-κB的功能激活，通过阻断氧化还原介导的NF-κB激活，降低TNF-α和FAs积累诱导的IL-6和IL-8的表达。在肝癌细胞中观察到的APE1过表达可能反映了对细胞损伤的适应性反应，并可能导致细胞进一步抵抗化疗和炎症反应的发生。抑制APE1氧化还原活性在阻断TNF-α和FAs诱导的炎症反应中的作用为炎症性肝病的治疗开辟了新的视角。
APE1/Ref-1 is a main regulator of cellular response to oxidative stress via DNA-repair function and co-activating activity on the NF-κB transcription factor. APE1 is central in controlling the oxidative stress-based inflammatory processes through modulation of cytokines expression and its overexpression is responsible for the onset of chemoresistance in different tumors including hepatic cancer. We examined the functional role of APE1 overexpression during hepatic cell damage related to fatty acid accumulation and the role of the redox function of APE1 in the inflammatory process. HepG2 cells were stably transfected with functional and non-functional APE1 encoding plasmids and the protective effect of APE1 overexpression toward genotoxic compounds or FAs accumulation, was tested. JHH6 cells were stimulated with TNF-α in the presence or absence of E3330, an APE1 redox inhibitor. IL-8 promoter activity was assessed by a luciferase reporter assay, gene expression by Real-Time PCR and cytokines (IL-6, IL-8, IL-12) levels measured by ELISA. APE1 over-expression did not prevent cytotoxicity induced by lipid accumulation. E3330 treatment prevented the functional activation of NF-κB via the alteration of APE1 subcellular trafficking and reduced IL-6 and IL-8 expression induced by TNF-α and FAs accumulation through blockage of the redox-mediated activation of NF-κB. APE1 overexpression observed in hepatic cancer cells may reflect an adaptive response to cell damage and may be responsible for further cell resistance to chemotherapy and for the onset of inflammatory response. The efficacy of the inhibition of APE1 redox activity in blocking TNF-α and FAs induced inflammatory response opens new perspectives for treatment of inflammatory-based liver diseases.
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