Glucocorticoids induce production of reactive oxygen species/reactive nitrogen species and DNA damage through an iNOS mediated pathway in breast cancer.
Glucocorticoids induce production of reactive oxygen species/reactive nitrogen species and DNA damage through an iNOS mediated pathway in breast cancer.
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DOI：
10.1186/s13058-017-0823-8
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发表时间：
2017-03-24
期刊：
影响因子：
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通讯作者：
Flint MS
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文献类型：
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作者：
Flaherty RL;Owen M;Fagan-Murphy A;Intabli H;Healy D;Patel A;Allen MC;Patel BA;Flint MS
心理压力会增加应激激素皮质醇和去甲肾上腺素（NE）的循环水平。长期暴露于升高的应激激素通过诱导DNA损伤与化疗反应降低有关。我们推测应激激素信号可能通过产生活性氧（ROS）/活性氮（RNS）和干扰DNA修复过程诱导DNA损伤，促进肿瘤发生。在存在和不存在受体拮抗剂和诱导型一氧化氮合酶（iNOS）抑制剂的情况下，将乳腺癌细胞系与生理水平的皮质醇和NE孵育，并使用磷酸化γ-H2 AX测量DNA损伤。使用彗星试验测量DNA修复速率，并使用电化学传感器检测来自暴露于应激激素的细胞的细胞裂解物中的ROS/RNS。使用同系小鼠模型来评估应激与对照动物中乳腺肿瘤中iNOS的存在，并使用蛋白质印迹和qRT-PCR检查iNOS的表达。急性暴露于皮质醇和NE显着增加的ROS/RNS和DNA损伤的水平，这种影响在受体拮抗剂的存在下被削弱。皮质醇诱导的DNA损伤和生产的RNS进一步衰减的iNOS抑制剂的存在下。在体内和皮质醇处理的细胞中观察到的心理应激反应中的iNOS的表达增加。抑制糖皮质激素受体相关的Src激酶也减少皮质醇诱导的RNS。这些结果表明，糖皮质激素可能以非基因组方式与iNOS相互作用，产生破坏性水平的RNS，从而使人们能够深入了解心理压力可能影响乳腺癌的潜在机制。本文的在线版本（doi：10.1186/s13058-017-0823-8）包含补充材料，可供授权用户使用。
Psychological stress increases the circulating levels of the stress hormones cortisol and norepinephrine (NE). Chronic exposure to elevated stress hormones has been linked to a reduced response to chemotherapy through induction of DNA damage. We hypothesize that stress hormone signalling may induce DNA damage through the production of reactive oxygen species (ROS)/reactive nitrogen species (RNS) and interference in DNA repair processes, promoting tumourigenesis. Breast cancer cell lines were incubated with physiological levels of cortisol and NE in the presence and absence of receptor antagonists and inducible nitric oxide synthase (iNOS) inhibitors and DNA damage measured using phosphorylated γ-H2AX. The rate of DNA repair was measured using comet assays and electrochemical sensors were used to detect ROS/RNS in the cell lysates from cells exposed to stress hormones. A syngeneic mouse model was used to assess the presence of iNOS in mammary tumours in stressed versus control animals and expression of iNOS was examined using western blotting and qRT-PCR. Acute exposure to cortisol and NE significantly increased levels of ROS/RNS and DNA damage and this effect was diminished in the presence of receptor antagonists. Cortisol induced DNA damage and the production of RNS was further attenuated in the presence of an iNOS inhibitor. An increase in the expression of iNOS in response to psychological stress was observed in vivo and in cortisol-treated cells. Inhibition of glucocorticoid receptor-associated Src kinase also produced a decrease in cortisol-induced RNS. These results demonstrate that glucocorticoids may interact with iNOS in a non-genomic manner to produce damaging levels of RNS, thus allowing an insight into the potential mechanisms by which psychological stress may impact breast cancer. The online version of this article (doi:10.1186/s13058-017-0823-8) contains supplementary material, which is available to authorized users.