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: 10302311
• 负责人: DARET K ST CLAIR
• 金额: $ 40.32万
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10302311
• 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120万例非黑色素瘤皮肤癌新增病例，包括鳞状细胞癌和 基底细胞癌，每年在美国被诊断出来， 超过了所有其他癌症的终生风险总和。紫外线（UV）辐射被认为是 非黑色素瘤皮肤癌的主要原因。目前预防紫外线辐射的范例 皮肤癌是应用一般的抗氧化产品，这是不够的，因为它是基于 对氧化应激在癌症发展中的作用的不完全理解。总的目标是 研究的目的是深入了解超氧自由基/阴离子（O2·-） ）在UVB致癌过程中的代谢转换，并测试概念 有针对性的抗氧化剂方法可以预防皮肤癌。我们的初步数据表明， 含锰超氧化物歧化酶（MnSOD）的表达受到抑制， 在肿瘤前阶段的组织学正常皮肤，这导致超氧化物产生增加， 解偶联蛋白（UCPs）的合成增加。此外，UCP的敲低抑制了 乳酸产生和增加ATP水平。因此，适应增加超氧化物的生产， UCP的诱导可能是导致瓦尔堡效应的关键步骤。我们还发现， 暴露于UVB引起MnSOD的硝化和失活，以及促存活自噬的激活 应答硝化MnSOD的免疫共沉淀鉴定了伴侣介导的 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 促进癌症发展和进展的致癌作用。具体目标1将测试 假设O2·-触发解偶联蛋白（UCP）依赖的代谢开关。具体目标2 将测试MnSOD是UVB诱导的过氧亚硝酸盐（OONO-）的一个至关重要的目标的假设。 ），导致自噬反应的激活。具体目标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。我们将使用分子遗传学 结合蛋白质组学的方法来鉴定UCP转录组和稳定同位素分辨 代谢组学，以确定导致肿瘤前代谢改变的途径。我们会好好利用- 表征MnSOD的模拟物，以测试机械靶向抗氧化剂可以 防止紫外线致癌。紫外线辐射和能量代谢之间的关系仍然存在 未知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 转化为代谢的脆弱性，而这些脆弱性是可以预防癌症的。