The Role of Polyamine Oxidase in Antitumor Drug Response

描述(由申请人提供)：本次更新的总体目标是测试我们最近克隆的精胺氧化酶(SMO)通过细胞内多胺氧化产生的活性氧物种在炎症相关肿瘤发生中发挥重要作用的假设。据估计，20-30%的上皮性癌症的病因与炎症直接相关。虽然许多炎症细胞、细胞因子和通路已被涉及，但将炎症和必要的致癌DNA突变联系起来的分子事件尚不清楚。我们最近发现的人类SMO可能提供了这样的联系。SMO是哺乳动物多胺分解代谢途径中的一个新成员。其活性产物为多胺、亚精胺、3-氨基丙醛和过氧化氢。我们已经证明，肿瘤特异性的精胺氧化酶活性的大幅增加可以导致肿瘤细胞的选择性死亡，从而为靶向抗肿瘤治疗提供了一种策略。然而，长期产生非细胞毒性水平的过氧化氢可能会对正常细胞产生有害影响，包括氧化DNA损伤导致突变。我们最近发现，多种刺激可以诱导多种上皮细胞发生SMO，包括幽门螺杆菌感染、肠毒素类脆弱类杆菌(ETBF)以及一般炎症介质、肿瘤坏死因子？、白介素1？IL-6和IL-8。幽门螺杆菌和脆弱芽孢杆菌分别与炎症相关的胃癌和结肠癌有关。肿瘤坏死因子的产生、释放和活性？而其他细胞因子是对炎症和损伤的常见反应。这些刺激都导致SMO表达增加，过氧化氢产生，可测量的DNA损伤被SMO的抑制所阻断，这一事实表明，多胺分解代谢酶SMO产生的ROS是将炎症和潜在的致癌DNA损伤联系起来的直接机制。因此，这些数据表明SMO可能是一个新的至关重要的化学预防靶点。因此，为了评估SMO作为化学预防治疗靶点的潜力，我们将：1)确定炎症刺激诱导SMO表达并产生DNA损伤的分子机制；2)单独使用脆弱杆菌APCMinAPC？716小鼠模型，并联合使用SMO和/或SMO敲除抑制剂，以确定细菌炎症、SMO活性、ROS产生和肿瘤发展之间是否存在直接联系。通过了解参与调控炎症诱导的SMO表达、过氧化氢产生和DNA损伤的途径，并通过确定它们在炎症相关上皮癌的发生和发展中的作用，很可能出现许多新的化学预防治疗靶点。公共卫生相关性：叙述性炎症与许多上皮性癌症的发展有关；然而，这种联系的分子基础尚不清楚。本申请的结果表明，精胺氧化酶(SMO)产生的过氧化氢是对肿瘤坏死因子？和其他炎症介质，作为炎症和潜在致癌DNA损伤之间的直接联系。更好地了解SMO在炎症诱导的癌症中的作用应该有助于制定预防癌症的治疗策略。

DESCRIPTION (provided by applicant): The overall objectives of this renewal are to test the hypothesis that production of reactive oxygen species through intracellular polyamine oxidation by our recently cloned spermine oxidase (SMO) plays a significant role in inflammation-associated tumorigenesis. It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation. Although many of the inflammatory cells, cytokines, and pathways have been implicated, the molecular events linking inflammation and the necessary carcinogenic DNA mutations are unknown. Our recently discovered human SMO may provide one such link. SMO is a new member of the mammalian polyamine catabolic pathway. The products of its activity are the polyamine, spermidine, 3-aminopropanal, and the reactive oxygen species, H2O2. We have demonstrated that large, tumor-specific increases of spermine oxidase activity can lead to selective tumor cell death, thus providing a strategy for targeted antitumor therapy. However, chronic production of non-cytotoxic levels of H2O2 can have deleterious effects on normal cells, including oxidative DNA damage leading to mutations. We have recently discovered that SMO is induced in several epithelial cell types by multiple stimuli including Helicobacter pylori infection, exposure to Enterotoxigenic Bacteroides fragilis (ETBF), and exposure to the general mediators of inflammation, TNF?, IL-1? IL-6, & IL8. Both H. pylori and B. fragilis are implicated in inflammation associated cancers, gastric and colon, respectively. The production, release, and activity of TNF? and other cytokines are common responses to inflammation and injury. The fact that these stimuli all lead to increased SMO expression, H2O2 production, and measurable DNA damage that is blocked by inhibition of SMO, suggest that ROS produced by the polyamine catabolic enzyme SMO is a direct mechanism linking inflammation and potentially carcinogenic DNA damage. Thus, these data indicate that SMO may represent a new and vitally important chemopreventive target. Therefore, to assess the potential of SMO as a target for chemopreventive therapy we will: 1) define the molecular mechanisms by which inflammatory stimuli induce the expression of SMO and produce DNA damage; 2) use a B. fragilis APCMinAPC?716 mouse model alone, and in combination with inhibitors of SMO and/or SMO knockout, to determine if a direct link exists between bacterial inflammation, SMO activity, ROS production and development of tumors. By understanding the pathways involved in regulating inflammation-induced SMO expression, H2O2 production, and DNA damage, and by defining their role in the initiation and progression of inflammation-associated epithelial cancers, it is likely that multiple new targets for chemopreventive therapy will emerge. PUBLIC HEALTH RELEVANCE: Narrative Inflammation is associated with the development of many epithelial cancers; however, the molecular basis of this association is not clearly understood. The results presented in this application implicate hydrogen peroxide produced by spermine oxidase (SMO) in response to TNF? and other mediators of inflammation, as a direct link between inflammation and potentially carcinogenic DNA damage. A better understanding of the role of SMO in inflammation-induced cancers should aid in treatment strategies to prevent cancer.