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120万例新的非黑色腺瘤皮肤癌病例，包括鳞状细胞癌和 碱性细胞癌，每年在美国诊断出来，以及皮肤癌的寿命风险 超过所有其他癌症的终身风险。紫外线（UV）辐射被认为是 非黑色素瘤皮肤癌的主要原因。当前预防UVB诱导的范式 皮肤癌是一般抗氧化剂产品的应用，这是不足的，因为它是基于 对氧化应激在癌症发展中的作用的不完全了解。总体目标 研究是为了深入了解超氧化物自由基/阴离子的机制（O2· - - ）在线粒体中，在UVB癌变期间有助于代谢转换并测试概念 靶向抗氧化剂方法可以预防皮肤癌。我们的初步数据表明 在 在肿瘤阶段的组织学正常皮肤，这会导致超氧化物产生增加和 增加的解偶联蛋白（UCP）的合成增加。此外，UCPS抑制抑制 乳酸产生并增加ATP水平。这是通过适应增加的超氧化物生产的 诱导UCP可能是导致Warburg效应的关键步骤。我们还发现 暴露于UVB会导致MNSOD的硝化和失活，并激活Prosurvival自噬 回答。硝酸MNSOD的共免疫沉淀确定的伴侣介导的成员 自噬（CMA）途径，该途径支持CMA在硝酸蛋白选择性降解中的作用。 基于这些新颖的发现，我们建议O2· - 是UVB代谢改变的关键驱动力 促进癌症发展和进展的致癌作用。特定目标1将测试 O2· - 触发依赖性代谢开关的解偶联蛋白（UCP）的假设。具体目标2 将检验以下假设：MNSOD是UVB诱导的过氧亚硝酸盐的至关重要的靶标（Oono-- ）导致自噬反应的激活。特定目标3将测试UVB引起的概念 O2·和Oono-是促进紫外致癌作用的关键介体。我们将使用分子遗传 方法与蛋白质组学结合以识别UCP转录组和稳定的异位素分辨 代谢组学鉴定导致额塑性代谢改变的途径。我们将使用良好 表征MNSOD的模拟物来检验机械靶向抗氧化剂可以 预防紫外线发生。紫外线辐射与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该知识差距，并提供宝贵的见解 进入预防癌症的代谢脆弱性。