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

超过120万新的非黑色素瘤皮肤癌病例，包括鳞状细胞癌和 在美国每年都会被诊断为基底细胞癌，皮肤癌的终身风险 超过了所有其他癌症的终生风险总和。紫外线辐射被认为是 非黑色素瘤皮肤癌的主要原因。当前预防UVB辐射的范例 皮肤癌是应用一般的抗氧化剂产品，这是不够的，因为它是基于 对氧化应激在癌症发生中的作用的认识不全面。这个项目的总体目标是 研究是为了深入了解超氧阴离子(O2·-) )参与了UVB致癌过程中的代谢转换，并验证了这一概念 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 癌前阶段组织学上正常的皮肤，导致超氧化物产生增加和 增加解偶联蛋白(UCP)的合成。此外，UCP的击倒抑制了 乳酸的产生和提高三磷酸腺苷水平。因此，通过以下方式适应增加的超氧化物生产 UCPs的诱导很可能是导致Warburg效应的关键步骤。我们还发现， 暴露于UVB可导致MnSOD硝化和失活，并激活存活期自噬 回应。硝化锰超氧化物歧化酶的免疫共沉淀法鉴定分子伴侣 自噬(CMA)途径，支持CMA在硝化蛋白质选择性降解中的作用。 基于这些新的发现，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。《特定目标1》将测试 假设O2·-触发依赖解偶联蛋白(UCP)的代谢开关。具体目标2 将检验这样一种假设，即MnSOD是UVB诱导的过氧亚硝酸盐(Oono-NO2-)的关键目标。 )，从而激活自噬反应。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 结合蛋白质组学方法鉴定UCP转录本和稳定同位素分辨 代谢组学，以确定导致癌前代谢改变的途径。我们会用好- 表征了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，并将提供有价值的见解 可以预防癌症的新陈代谢的脆弱性。

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.