Matschke Johann, Riffkin Helena, Klein Diana, Handrick René, Lüdemann Lutz, Metzen Eric, Shlomi Tomer, Stuschke Martin, Jendrossek Verena
1 Institute of Cell Biology (Cancer Research), University Hospital Essen , Essen, Germany .
2 Institute of Applied Biotechnology (IAB), University of Applied Sciences , Biberach, Germany .
Antioxid Redox Signal. 2016 Jul 10;25(2):89-107. doi: 10.1089/ars.2015.6589. Epub 2016 May 9.
Tumor hypoxia is a major biological factor causing poor patient outcome. Evidence is increasing that improved protection against reactive oxygen species (ROS) participates in therapy resistance of chronically hypoxic cancer cells. We aimed at characterizing the relevance of improved ROS defense for radiation resistance of cancer cells with tolerance to cycling anoxia/re-oxygenation stress ("anoxia-tolerant") and at designing rational treatment strategies for overcoming the resulting therapy resistance by targeting the underlying mechanisms identified in an in vitro model.
We demonstrate that chronic exposure of NCH-H460 lung adenocarcinoma, DU145 prostate cancer, and T98G glioblastoma cells to cycling anoxia/re-oxygenation stress induced upregulation of the aspartate-aminotransferase glutamic-oxaloacetic transaminase (GOT1), particularly in RAS-driven anoxia-tolerant NCI-H460 cells. Altered glutamine utilization of the anoxia-tolerant cancer cells contributed to the observed decrease in cellular ROS levels, the increase in cellular glutathione levels, and improved cell survival on ROS-inducing treatments, including exposure to ionizing radiation. Importantly, targeting glutamine-dependent antioxidant capacity or glutathione metabolism allowed us to hit anoxia-tolerant cancer cells and to overcome their increased resistance to radiation-induced cell death. Targeting glutathione metabolism by Piperlongumine also improved the radiation response of anoxia-tolerant NCI-H460 cells in vivo.
Improved antioxidant capacity downstream of up-regulated GOT1-expression is a characteristic of anoxia-tolerant cancer cells and is predictive for a specific vulnerability to inhibition of glutamine utilization or glutathione metabolism, respectively.
Unraveling the molecular alterations underlying improved ROS defense of anoxia-tolerant cancer cells allows the design of rational strategies for overcoming radiation resistance caused by tumor cell heterogeneity in hypoxic tumors. Antioxid. Redox Signal. 25, 89-107.
肿瘤缺氧是导致患者预后不良的主要生物学因素。越来越多的证据表明，增强对活性氧（ROS）的防护参与了慢性缺氧癌细胞的治疗抵抗。我们旨在确定增强的ROS防御对耐受循环性缺氧/复氧应激（“耐缺氧”）的癌细胞辐射抗性的相关性，并通过靶向体外模型中确定的潜在机制，设计合理的治疗策略来克服由此产生的治疗抵抗。
我们证明，将NCH-H460肺腺癌、DU145前列腺癌和T98G胶质母细胞瘤细胞长期暴露于循环性缺氧/复氧应激中，会诱导天冬氨酸转氨酶-谷氨酸草酰乙酸转氨酶（GOT1）上调，尤其是在RAS驱动的耐缺氧NCI-H460细胞中。耐缺氧癌细胞谷氨酰胺利用的改变导致观察到的细胞内ROS水平降低、细胞内谷胱甘肽水平升高，以及在包括电离辐射在内的ROS诱导治疗下细胞存活率提高。重要的是，靶向谷氨酰胺依赖性抗氧化能力或谷胱甘肽代谢使我们能够靶向耐缺氧癌细胞，并克服它们对辐射诱导的细胞死亡的增强抗性。胡椒碱靶向谷胱甘肽代谢也改善了耐缺氧NCI-H460细胞在体内的辐射反应。
上调的GOT1表达下游增强的抗氧化能力是耐缺氧癌细胞的一个特征，分别预测了对谷氨酰胺利用或谷胱甘肽代谢抑制的特定易感性。
揭示耐缺氧癌细胞增强ROS防御背后的分子改变，有助于设计合理的策略来克服缺氧肿瘤中肿瘤细胞异质性导致的辐射抗性。《抗氧化与氧化还原信号》25卷，89 - 107页。
