The Role of Polyamine Oxidase in Antitumor Drug Response

摘要 这一更新的总体目标是检验活性氧的产生 通过我们最近克隆的精胺氧化酶（SMO）的细胞内多胺氧化， 在炎症相关肿瘤发生中的作用。据估计，20-30%的上皮癌的病因 与炎症直接相关。尽管许多炎症细胞，细胞因子和途径 已经被牵连，分子事件连接炎症和必要的致癌DNA 突变是未知的。我们最近发现的人类SMO可能提供了一个这样的联系。SMO是一个新的 哺乳动物多胺分解代谢途径的成员。其活性产物为多胺， 亚精胺，3-氨基丙醛，和活性氧，H2 O2。我们已经证明， 精胺氧化酶活性的肿瘤特异性增加可导致选择性肿瘤细胞死亡，从而提供了一种治疗肿瘤的方法。 靶向抗肿瘤治疗策略。然而，非细胞毒性水平的H2 O2的慢性产生可能具有 对正常细胞的有害影响，包括导致突变的氧化DNA损伤。我们最近 发现SMO在几种上皮细胞类型中被多种刺激诱导，包括幽门螺杆菌 感染、暴露于致肠炎性脆弱类杆菌（ETBF）和暴露于 炎症、TNF、IL-1、IL-6和IL 8。两个都是H. pylori和B.脆弱性与炎症相关 胃癌和结肠癌。肿瘤坏死因子和其他细胞因子的产生、释放和活性是 对炎症和损伤的常见反应。事实上，这些刺激都导致增加SMO 表达、H2 O2产生和通过抑制SMO而阻断的可测量的DNA损伤表明， 由多胺分解代谢酶SMO产生的ROS是连接炎症和炎症的直接机制。 可能致癌的DNA损伤因此，这些数据表明，SMO可能代表了一种新的， 重要化学预防靶点。因此，为了评估SMO作为化学预防靶点的潜力， 我们将：1）确定炎症刺激诱导表达的分子机制， SMO并产生DNA损伤; 2）使用B。fragilis APC+/-MinAPC <$716小鼠模型，单独和组合 与SMO抑制剂和/或SMO敲除，以确定细菌炎症， SMO活性、ROS产生和肿瘤发展。通过了解参与的途径 调节炎症诱导的SMO表达、H2 O2产生和DNA损伤，并通过定义它们的 在炎症相关上皮癌的发生和发展中的作用，很可能是多个新的 化学预防治疗的目标将会出现。

Abstract 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 SMOmay 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 typesby 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 APC+/-MinAPC¿716 mouse model alone, and in combination with inhibitors of SMO and/or SMO knockout, to determine if a direct link exists between bacterialinflammation, 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.