A redox-mediated mechanism of UVB-induced metabolic switch in skin carcinogenesis

UVB 诱导的皮肤癌代谢转换的氧化还原介导机制

• 批准号: 10054169
• 负责人: DARET K ST CLAIR
• 金额: $ 41.14万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-18 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054169
• 关键词: Affinity; Anions; Antioxidants; Autophagocytosis; Basal cell carcinoma; Bioenergetics; Chemistry; Chemoprevention; Co-Immunoprecipitations; Consumption; Coupled; Data; Development; Diagnosis; Energy Metabolism; Epithelial Cells; Event; Exposure to; Genetic Enhancer Element; Genetic Transcription; Glucose; Glycolysis; Goals; Histologic; Human; Intervention; Kinetics; Knowledge; Luciferases; Malignant Epithelial Cell; Malignant Neoplasms; Manganese; Mediating; Mediator of activation protein; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Molecular Biology; Molecular Chaperones; Molecular Genetics; Normal tissue morphology; Ontology; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Peroxonitrite; Prevention; Production; Proteins; Proteomics; Reporter Genes; Research; Risk; Role; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Squamous cell carcinoma; Superoxide Dismutase; Superoxides; Testing; Tissues; Transgenic Mice; UV carcinogenesis; UV induced; UVB carcinogenesis; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; United States; Validation; Warburg Effect; base; cancer prevention; carcinogenesis; design; genetic approach; insight; knock-down; lifetime risk; member; metabolomics; mimetics; nitration; novel; prevent; promoter; prototype; response; skin cancer prevention; stable isotope; transcriptome; tumor

More than 1.2 million new cases of non-melanoma skin cancer, including squamous cell carcinoma and basal cell carcinoma, are diagnosed annually in the United States, and the lifetime risk for skin cancer exceeds the lifetime risk for all other cancers combined. Ultraviolet (UV) radiation is considered as the main cause of non-melanoma skin cancer. The current paradigm for prevention against UVB-induced skin cancer is application of general antioxidant products, which is inadequate because it is based on incomplete understanding of the role of oxidative stress in cancer development. The overall goal of this research is to gain an in-depth understanding of the mechanism by which superoxide radical/anion (O2·- ) in mitochondria contributes to metabolic switch during UVB carcinogenesis and to test the concept that a targeted antioxidant approach can prevent skin cancer. Our preliminary data demonstrate that the expression of manganese containing superoxide dismutase (MnSOD) is suppressed in histologically normal skin at preneoplastic stage, which results in increased superoxide production and increased synthesis of uncoupling proteins (UCPs). Furthermore, knockdown of UCPs suppresses lactate production and increases ATP levels. Thus, adaptation to increased superoxide production by induction of UCPs is likely the critical step leading to the Warburg effect. We also have found that exposure to UVB causes nitration and inactivation of MnSOD, and activation of prosurvival autophagy responses. Co-immunoprecipitation of nitrated MnSOD identified members of the Chaperone-Mediated Autophagy (CMA) pathway, which supports the role of CMA in selective degradation of nitrated proteins. Based on these novel findings, we propose that O2·- is a critical driver of metabolic alteration in UVB carcinogenesis that promotes cancer development and progression. Specific Aim 1 will test the hypothesis that O2·- triggers an uncoupling protein (UCP)-dependent metabolic switch. Specific Aim 2 will test the hypothesis that MnSOD is a critically important target of UVB-induced peroxynitrite (OONO- ) that leads to activation of autophagy responses. Specific Aim 3 will test the concept that UVB-induced O2·- and OONO- are critical mediators that promote UV carcinogenesis. We will use molecular genetic approach coupled with proteomics to identify UCP transcriptomes and stable-isotope-resolved metabolomics to identify pathways leading to preneoplastic metabolic alterations. We will use well- characterized mimetics of MnSOD to test the concept that mechanistically targeted antioxidants can prevent UV carcinogenesis. The relationship between UV radiation and energy metabolism remains unknown. The results from this study will close that knowledge gap and will provide valuable insights into the metabolic vulnerabilities that are amenable to cancer prevention.

超过 120 万新发非黑色素瘤皮肤癌病例，包括鳞状细胞癌和 细胞癌，在美国每年诊断一次，以及终生患皮肤癌的基本风险 超过所有其他癌症的终生风险的总和。 当前预防 UVB 诱发的范例。 皮肤癌是一般抗氧化产品的应用，这是不够的，因为它基于 对氧化应激在癌症发展中的作用的了解不完全。 研究目的是深入了解超氧自由基/阴离子（O2·- ）在线粒体中有助于 UVB 致癌过程中的代谢转换并测试这一概念 我们的初步数据表明，有针对性的抗氧化方法可以预防皮肤癌。 含锰超氧化物歧化酶 (MnSOD) 的表达受到抑制 肿瘤前阶段组织学正常的皮肤，导致超氧化物产生增加 解偶联蛋白（UCP）的合成增加。 乳酸的产生并增加 ATP 水平因此，通过适应增加的超氧化物产生。 UCP 的诱导可能是导致 Warburg 效应的关键步骤。 暴露于 UVB 会导致 MnSOD 硝化和失活，并激活促存活自噬 硝化 MnSOD 的免疫共沉淀鉴定出分子伴侣介导的成员。 自噬 (CMA) 途径，支持 CMA 在选择性降解硝化蛋白质中的作用。 基于这些新发现，我们提出 O2·- 是 UVB 代谢改变的关键驱动因素 促进癌症发生和进展的致癌作用具体目标 1 将测试 假设 O2·- 触发解偶联蛋白 (UCP) 依赖性代谢开关。 具体目标 2。 将检验以下假设：MnSOD 是 UVB 诱导的过氧亚硝酸盐 (OONO- ）导致自噬反应的激活特定目标 3 将测试 UVB 诱导的概念。 O2·- 和 OONO- 是促进紫外线致癌的关键介质，我们将利用分子遗传学。 与蛋白质组学相结合的方法来识别 UCP 转录组和稳定同位素解析 我们将利用代谢组学来识别导致肿瘤前代谢改变的途径。 MnSOD 的模拟物的特征，以测试机械靶向抗氧化剂可以 预防紫外线致癌 紫外线辐射与能量代谢之间的关系仍然存在。 这项研究的结果将缩小这一知识差距，并提供有价值的见解。 研究适合预防癌症的代谢脆弱性。