INSERM U701, German Cancer Research Centre, Program Infection and Cancer, INF 242, Heidelberg, Germany.
Glia. 2012 Nov;60(11):1785-800. doi: 10.1002/glia.22397. Epub 2012 Aug 1.
The high intratumoral and intertumoral heterogeneity of glioblastoma (GBM) leads to resistance to different therapies, and hence, selecting an effective therapy is very challenging. We hypothesized that the antioxidant enzyme status is a significant feature of GBM heterogeneity. The most important reactive oxygen/nitrogen species (ROS/RNS) detoxification mechanisms include superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx). Expression and activity of these enzymes and the cellular response to induced oxidative stress were systematically analyzed and compared between GBM cells and nontransformed glial cells of both human and murine origin. Regardless of cell type or species, all tested cells expressed similar amount of catalase and MnSOD. All except one, GBM cell lines exhibited a deficiency in GPx1 expression and activity. Analysis of GBM tissue sections indicated a heterogeneous profile of weak to moderate expression of GPx1 in tumor cells. GPx1 deficiency led to an accumulation of ROS/RNS and subsequent death of GBM cells after induction of oxidative stress. Astrocytes, microglia/macrophages, and glioma stem cell lines expressed active GPx1 and resisted ROS/RNS-mediated cell death. Pharmacological inhibition or siRNA silencing of GPx1 partially reverted this resistance in astrocytes, indicating the contribution of various antioxidant molecules besides GPx1. The GPx1-expressing GBM cell line on the contrary, became extremely sensitive to oxidative stress after GPx1 inhibition. Altogether, these results highlight GPx1 as a crucial element over other antioxidant enzymes for oxidative stress regulation in GBM cells. Mapping the antioxidant enzyme status of GBM may prove to be a useful tool for personalized ROS/RNS inducing therapies.
胶质母细胞瘤（GBM）的肿瘤内和肿瘤间异质性很高，导致对不同治疗方法的耐药性，因此，选择有效的治疗方法非常具有挑战性。我们假设抗氧化酶状态是 GBM 异质性的一个重要特征。最重要的活性氧/氮物种（ROS/RNS）解毒机制包括超氧化物歧化酶（SOD）、过氧化氢酶和谷胱甘肽过氧化物酶（GPx）。我们系统地分析和比较了这些酶的表达和活性以及细胞对诱导氧化应激的反应，比较了来源于人和鼠的 GBM 细胞和非转化神经胶质细胞。无论细胞类型或物种如何，所有测试的细胞都表达了相似数量的过氧化氢酶和 MnSOD。除了一个之外，所有 GBM 细胞系都表现出 GPx1 表达和活性的缺乏。对 GBM 组织切片的分析表明，肿瘤细胞中 GPx1 的表达呈弱至中度的异质性。GPx1 缺乏导致 ROS/RNS 的积累，随后在诱导氧化应激后导致 GBM 细胞死亡。星形胶质细胞、小胶质细胞/巨噬细胞和神经胶质瘤干细胞系表达活性 GPx1，并抵抗 ROS/RNS 介导的细胞死亡。GPx1 的药理学抑制或 siRNA 沉默部分逆转了星形胶质细胞中的这种耐药性，表明除了 GPx1 之外，各种抗氧化分子都有贡献。相反，表达 GPx1 的 GBM 细胞系在 GPx1 抑制后对氧化应激变得极其敏感。总之，这些结果强调了 GPx1 作为调节 GBM 细胞中氧化应激的其他抗氧化酶的关键因素。对 GBM 的抗氧化酶状态进行映射可能被证明是一种用于个性化 ROS/RNS 诱导治疗的有用工具。
