Catalase down-regulation in cancer cells exposed to arsenic trioxide is involved in their increased sensitivity to a pro-oxidant treatment.
Catalase down-regulation in cancer cells exposed to arsenic trioxide is involved in their increased sensitivity to a pro-oxidant treatment.
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DOI：
10.1186/s12935-018-0524-0
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发表时间：
2018
影响因子：
5.8
通讯作者：
Calderon PB
中科院分区：
文献类型：
--
作者：
Glorieux C;Calderon PB
已提出促氧化剂药物用于治疗某些癌症，但癌细胞对氧化应激产生的抗性限制了其在临床上的潜在用途。为了了解抗氧化应激的潜在机制，我们发现长期暴露于H2 O2生成系统（抗坏血酸/甲萘醌，Asc/Men）或过氧化氢酶过表达（CAT 3细胞）增加了癌细胞对氧化应激的抵抗力，可能是通过增加癌细胞的抗氧化状态。过氧化氢酶表达的调节通过蛋白质过表达或蛋白质下调使用针对过氧化氢酶的siRNA和氨基三唑作为药理学抑制剂来进行。前一种方法通过用含有人过氧化氢酶cDNA的质粒构建体（CAT 3细胞，来源于MCF-7乳腺癌细胞系）转染细胞或通过长期暴露于氧化剂损伤产生抗性细胞（Resox细胞）来完成。通过使用MTT还原测定和进一步计算IC 50值来监测细胞存活。蛋白质表达通过蛋白质印迹法进行。通过流式细胞术进行活性氧簇的形成。通过使用含有− 1518/+ 16启动子结构域的质粒转染细胞来评估人过氧化氢酶启动子的转录活性。使用Resox和CAT 3细胞（来自MCF-7乳腺癌细胞系）作为癌症对促氧化治疗的抗性的模型，我们发现三氧化二砷（ATO）显著地使Resox和CAT 3细胞对Asc/Men治疗敏感。由于过氧化氢酶是一种关键的抗氧化酶，参与解毒Asc/Men（如siRNA介导的过氧化氢酶敲低所示），在抗性细胞中过表达，我们假设ATO可能调节过氧化氢酶的表达水平。一致地，当与ATO孵育时，Resox细胞中的过氧化氢酶蛋白水平降低，可能是由于过氧化氢酶启动子的转录活性降低。我们的研究结果支持ATO应与促氧化剂药物联合给药以增强实体瘤中癌细胞死亡的建议。
Pro-oxidant drugs have been proposed for treating certain cancers but the resistance developed by cancer cells to oxidative stress limits its potential use in clinics. To understand the mechanisms underlying resistance to oxidative stress, we found that the chronic exposure to an H2O2-generating system (ascorbate/menadione, Asc/Men) or catalase overexpression (CAT3 cells) increased the resistance of cancer cells to oxidative stress, likely by increasing the antioxidant status of cancer cells. Modulation of catalase expression was performed by either protein overexpression or protein down-regulation using siRNA against catalase and aminotriazole as pharmacological inhibitor. The former approach was done by transfecting cells with a plasmid construct containing human catalase cDNA (CAT3 cells, derived from MCF-7 breast cancer cell line) or by generating resistant cells through chronic exposure to an oxidant injury (Resox cells). Cell survival was monitored by using the MTT reduction assay and further calculation of IC50 values. Protein expression was done by Western blots procedures. The formation of reactive oxygen species was performed by flow cytometry. The transcriptional activity of human catalase promoter was assessed by using transfected cells with a plasmid containing the − 1518/+ 16 promoter domain. Using Resox and CAT3 cells (derived from MCF-7 breast cancer cell line) as models for cancer resistance to pro-oxidative treatment, we found that arsenic trioxide (ATO) remarkably sensitized Resox and CAT3 cells to Asc/Men treatment. Since catalase is a key antioxidant enzyme involved in detoxifying Asc/Men (as shown by siRNA-mediated catalase knockdown) that is overexpressed in resistant cells, we hypothesized that ATO might regulate the expression levels of catalase. Consistently, catalase protein level is decreased in Resox cells when incubated with ATO likely by a decreased transcriptional activity of the catalase promoter. Our findings support the proposal that ATO should be administered in combination with pro-oxidant drugs to enhance cancer cell death in solid tumors.
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影响因子：
11.2
作者：
Fiskus W;Coothankandaswamy V;Chen J;Ma H;Ha K;Saenz DT;Krieger SS;Mill CP;Sun B;Huang P;Mumm JS;Melnick AM;Bhalla KN
通讯作者：
Bhalla KN
影响因子：
3.4
作者：
Beck, Raphael;Pedrosa, Rozangela Curi;Verrax, Julien
通讯作者：
Verrax, Julien
影响因子：
20.3
作者：
Chendamarai, Ezhilarasi;Balasubramanian, Poonkuzhali;Mathews, Vikram
通讯作者：
Mathews, Vikram
影响因子：
6.5
作者：
Bachleitner-Hofmann, T;Gisslinger, B;Gisslinger, H
通讯作者：
Gisslinger, H
DOI：
10.1073/pnas.0306687101
发表时间：
2004-03-30
影响因子：
11.1
作者：
Chou, WC;Jie, CF;Dang, CV
通讯作者：
Dang, CV