School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia.
Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia.
Sci Rep. 2017 Nov 9;7(1):15140. doi: 10.1038/s41598-017-15474-7.
One of the hallmarks of the tumour microenvironment is hypoxia resulting from increased oxygen consumption by proliferative cancer cells and altered vasculature. Hypoxic tension initiates various cellular signals and can drive epithelial to mesenchymal transition (EMT), a process important in cancer progression. In this study, using the antioxidant N-acetylcysteine (NAC), we show that hypoxia-induced reactive oxygen species (ROS) in MDA-MB-468 breast cancer cells, selectively regulate hypoxia-induced increases in N-cadherin and SERPINE1, two proteins involved in cell adhesion. Treatment of cells with NAC also attenuated hypoxia-mediated activation of EGFR, but did not have any effect on hypoxia-mediated induction of HIF1α. Exogenous hydrogen peroxide phenocopied the effects of hypoxia on N-cadherin and SERPINE1 expression and EGFR activation, suggesting its possible involvement in these hypoxia-mediated events. Reflective of their effect on cell adhesion proteins and EGFR (associated with migratory phenotypes), NAC also reduced cell migration under hypoxic conditions, a crucial event in metastasis. Our findings suggest a selective role for redox signalling in the regulation of specific components of the responses to hypoxia and induction of EMT in breast cancer cells. This study provides new evidence supporting the potential of targeting ROS as a therapeutic strategy for the control of breast cancer metastasis.
肿瘤微环境的一个标志是缺氧，这是由于增殖癌细胞耗氧量增加和血管改变导致的。缺氧张力引发各种细胞信号，并能驱动上皮细胞向间充质转化（EMT），这是癌症进展中的一个重要过程。在这项研究中，我们使用抗氧化剂 N-乙酰半胱氨酸（NAC）表明，MDA-MB-468 乳腺癌细胞中的缺氧诱导的活性氧（ROS）选择性调节缺氧诱导的 N-钙粘蛋白和 SERPINE1 的增加，这两种蛋白参与细胞黏附。用 NAC 处理细胞也能减弱缺氧介导的 EGFR 激活，但对缺氧介导的 HIF1α诱导没有任何影响。外源性过氧化氢模拟了缺氧对 N-钙粘蛋白和 SERPINE1 表达和 EGFR 激活的影响，表明其可能参与这些缺氧介导的事件。NAC 还降低了缺氧条件下的细胞迁移，这是转移的关键事件，反映了它们对细胞黏附蛋白和 EGFR（与迁移表型相关）的影响。我们的发现表明，氧化还原信号在调节乳腺癌细胞对缺氧反应和 EMT 诱导的特定成分方面具有选择性作用。这项研究为靶向 ROS 作为控制乳腺癌转移的治疗策略提供了新的证据。
