Flint Melanie S, Baum Andrew, Chambers William H, Jenkins Frank J
Department of Psychology, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.
Psychoneuroendocrinology. 2007 Jun;32(5):470-9. doi: 10.1016/j.psyneuen.2007.02.013. Epub 2007 Apr 24.
Stress is associated with increased production of sympathetic and other adrenal hormones. Epinephrine (E), norepinephrine (NE) and cortisol are produced during psychological stress and may affect many cells directly. These effects may be transient (e.g. heart rate, immune cell trafficking) or they can have more long-lasting consequences, such as permanent DNA damage which may result in increased cell transformation and/or tumorigenicity. Here, the molecular effects of short term in vitro exposure of these stress hormones were analyzed on murine 3T3 cells by measuring effects on DNA damage and repair, cell transformation and changes in mRNA expression of genes specifically involved in DNA damage signaling pathways. Short-term exposure (<30 min) to physiological concentrations of either cortisol, NE or E induced at least five-fold increases in DNA damage in treated cells compared to untreated controls. Pre-treatment with blocking agents such as the glucocorticoid receptor antagonist RU486, or the beta-adrenergic receptor antagonist propranolol, eliminated this increase in damage. Both cortisol and NE interfered with repair of DNA damage in cells exposed to UV and resulted in an increase in the transformed phenotype. In contrast, E had none of these effects on 3T3 cells. Stress hormones had no significant effects on cell cycle regulation. Targeted gene arrays showed that cortisol, NE and E modulated the transcription of 21, 14 and 18 genes, respectively. These genes were directly related to DNA damage signaling pathways, and included up-regulation of DNA damage sensors Chk1 and Chk2, and the proto-oncogene CDC25A, which is involved in cell cycle delay following DNA damage. Taken together, these data show that stress hormones can increase DNA damage and transformation and alter transcriptional regulation of the cell cycle.
压力与交感神经及其他肾上腺激素分泌增加有关。心理压力期间会产生肾上腺素（E）、去甲肾上腺素（NE）和皮质醇，它们可能直接影响许多细胞。这些影响可能是短暂的（如心率、免疫细胞运输），也可能产生更持久的后果，如永久性DNA损伤，这可能导致细胞转化增加和/或致癌性增强。在此，通过测量对DNA损伤与修复、细胞转化以及DNA损伤信号通路中特定基因mRNA表达变化的影响，分析了这些应激激素在体外短期作用于小鼠3T3细胞的分子效应。与未处理的对照相比，短期暴露（<30分钟）于生理浓度的皮质醇、NE或E可使处理细胞中的DNA损伤增加至少五倍。用糖皮质激素受体拮抗剂RU486或β-肾上腺素能受体拮抗剂普萘洛尔等阻断剂预处理可消除这种损伤增加。皮质醇和NE均干扰暴露于紫外线的细胞中DNA损伤的修复，并导致转化表型增加。相比之下，E对3T3细胞没有这些影响。应激激素对细胞周期调控没有显著影响。靶向基因阵列显示，皮质醇、NE和E分别调节21、14和18个基因的转录。这些基因与DNA损伤信号通路直接相关，包括DNA损伤传感器Chk1和Chk2以及原癌基因CDC25A的上调，后者参与DNA损伤后的细胞周期延迟。综上所述，这些数据表明应激激素可增加DNA损伤和转化，并改变细胞周期的转录调控。
