N-acetylcysteine potentiates doxorubicin-induced ATM and p53 activation in ovarian cancer cells.
N-acetylcysteine potentiates doxorubicin-induced ATM and p53 activation in ovarian cancer cells.
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DOI：
10.3892/ijo.2012.1680
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发表时间：
2013-01
影响因子：
5.2
通讯作者：
Wan Y
中科院分区：
文献类型：
--
作者：
Brum G;Carbone T;Still E;Correia V;Szulak K;Calianese D;Best C;Cammarata G;Higgins K;Ji F;Di W;Wan Y
多柔比星已在临床上用于治疗各种类型的癌症，但多柔比星的分子作用模式仍有待完全阐明。在这项研究中，我们研究了阿霉素对培养的卵巢癌细胞（CaOV3）的影响。MTT法显示阿霉素对细胞增殖的抑制作用具有时间和剂量依赖性。吞噬动力学细胞运动试验数据表明，阿霉素抑制CaOV3细胞的基础水平和EGF诱导的细胞迁移。共聚焦显微镜数据显示，阿霉素诱导重组的细胞骨架蛋白，包括肌动蛋白，微管蛋白和波形蛋白。阿霉素诱导p53在Ser15和20的磷酸化、p53的乙酰化和ATM活化。阿霉素还诱导组蛋白H2AX在Ser139处的磷酸化。有趣的是，阿霉素也抑制mTOR活性，通过S6核糖体蛋白的磷酸化来测量。用抗氧化剂N-乙酰半胱氨酸（NAC）而不是吡咯烷二硫代氨基甲酸酯（PDTC）预处理CaOV3细胞可增强阿霉素诱导的p53和ATM磷酸化。总的来说，我们得出结论，阿霉素诱导ATM/p53激活，导致重组的细胞骨架网络，抑制mTOR活性，抑制细胞增殖和迁移。我们的数据还表明，通过抗氧化剂（例如NAC）去除氧化剂可能会增强阿霉素在体内的功效。
Doxorubicin has been used clinically to treat various types of cancer, and yet the molecular mode of actions of doxorubicin remains to be fully unraveled. In this study, we investigated the effect of doxorubicin on cultured ovarian cancer cells (CaOV3). MTT assay data showed that doxorubicin inhibits cell proliferation in a time- and dose-dependent manner. Phagokinetic cell motility assay data indicated that doxorubicin inhibits both basal level and EGF-induced cell migration in CaOV3 cells. Confocal microscopic data revealed that doxorubicin induces reorganization of cytoskeletal proteins including actin, tubulin and vimentin. Doxorubicin induces phosphorylation of p53 at Ser15 and 20, acetylation of p53 and ATM activation. Doxorubicin also induces phosphorylation of histone H2AX at Ser139. Interestingly, doxorubicin also inhibits mTOR activity, measured by phosphorylation of S6 ribosomal protein. Pretreatment of CaOV3 cells with antioxidant N-acetylcysteine (NAC), but not pyrrolidine dithiocarbamate (PDTC) potentiates doxorubicin-induced phosphorylation of p53 and ATM. Collectively, we conclude that doxorubicin induces ATM/p53 activation leading to reorganization of cytoskeletal networks, inhibition of mTOR activity, and inhibition of cell proliferation and migration. Our data also suggest that removal of oxidants by antioxidants such as NAC may enhance the efficacy of doxorubicin in vivo.
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影响因子：
8
作者：
Ashley N;Poulton J
通讯作者：
Poulton J
影响因子：
5.8
作者：
Bijman, Marcel N. A.;van Berkel, Maria P. A.;Boven, Epie
通讯作者：
Boven, Epie
影响因子：
11.2
作者：
Jaamaa, Sari;af Hallstrom, Taija M.;Laiho, Marikki
通讯作者：
Laiho, Marikki
影响因子：
1
作者：
Grzanka, Dariusz;Marszalek, Andrzej;Grzanka, Alina
通讯作者：
Grzanka, Alina
影响因子：
3.9
作者：
Bagriacik, E. Umit;Uslu, Kadriye;Karasu, Cimen
通讯作者：
Karasu, Cimen