蛋白质氧化还原性修饰在皮肤癌发生发展过程中作用和相关机制的研究

Protein redox modification by reactive free radicals (ROS) is thought to be a common pathogenic factor for many types of disease including cancer. Previously, we demonstrated that deficiency of MnSOD, a primary antioxidant enzyme located in mitochondria, essentially increases the production of ROS leading to the activation of oncogenic signaling pathways. The reduction of MnSOD consequently mediates up-regulation of mitochondrial uncoupling proteins (UCPs) resulting in decreased ATP production through mitochondrial electron transport chain. Impaired mitochondrial function eventually enhances cellular energy metabolism reprogramming to use glycolytic pathway for cell survival. We hypothesize therefore: (1) as an important upstream of cell signaling, redox signaling regulates other cell signaling pathways including phosphorylation, and (2) declined antioxidant capacity plays a causal role in tumorigenesis by switching cell energy metabolism from mitochondrial oxidative phosphorylation to glycolysis. To testify our hypotheses, we propose to investigate protein redox modification and its role in alteration of other cell signaling pathways using our UVB-induced MnSOD-deficient mouse skin carcinoma model. In addition, parthenolide dramatically enhances radiosensitivity of tumor tissues but protects normal tissues from radiotoxicity by reversely modulating redox status in cancer cells vs. normal cells. To enhance sensitivity of skin tumors to radiation by manipulation of cellular redox status, we propose to use a water-soluble analogue of parthenolide, DMAPT for the improvement of radiotherapy of skin cancer.

活性氧自由基(ROS)导致蛋白质氧化性修饰是肿瘤的致病因子。在抗氧化酶MnSOD缺陷型细胞中，我们发现ROS诱导活化致癌信号通路，上调线粒体解偶联蛋白UCPs表达, 导致线粒体电子传递链与ATP合成解偶联，能量代谢从线粒体氧化磷酸化向糖酵解旁路倾斜。据此我们推论：（1）氧化还原信息影响制约其它细胞信号通路；（2）抗氧化能力下降造成的细胞能量代谢途径改变驱动了肿瘤发生。本课题拟采用紫外线诱导MnSOD缺陷性裸鼠皮肤癌模型，分析敏感性蛋白质氧化还原性修饰及由其诱发的磷酸化修饰，并通过调控蛋白质氧化还原性修饰抑制肿瘤发生和增加肿瘤细胞对放疗的敏感性。Parthenolide，一种氧化还原调节剂，可通过反向调节肿瘤细胞和正常细胞中蛋白质氧化还原修饰状态，选择性地增加肿瘤放疗效果且减低放疗对正常组织器官的损伤。因此，本课题拟使用其水溶性衍生物DMAPT作为放疗的辅助剂，以增加放疗对皮肤癌的控制效果。