The Role of Polyamine Oxidase in Antitumor Drug Response

摘要 这次更新的总体目标是检验这样一种假设，即产生的活性氧物种 我们最近克隆的精胺氧化酶(SMO)通过细胞内的多胺氧化发挥了重要的作用 在炎症相关肿瘤发生中的作用。据估计，20%-30%的上皮性癌症的病因 与炎症直接相关。尽管许多炎症细胞、细胞因子和途径 已经牵涉到，将炎症和必要的致癌DNA联系起来的分子事件 突变是未知的。我们最近发现的人类SMO可能提供了这样的联系。SMO是一种新的 哺乳动物多胺分解代谢途径的成员。其活性产物是多胺， 亚精胺，3-氨基丙醛，和活性氧物种，过氧化氢。我们已经证明了这种巨大的， 肿瘤特异性的精胺氧化酶活性增加可导致选择性肿瘤细胞死亡，从而提供一种 靶向抗肿瘤治疗的策略。然而，慢性产生的非细胞毒性水平的过氧化氢可能会 对正常细胞的有害影响，包括导致突变的氧化DNA损伤。我们最近做了 发现包括幽门螺杆菌在内的多种刺激可在多种上皮细胞中诱导SMO 感染，暴露于产肠毒素脆弱类杆菌(ETBF)，以及暴露于一般介体 炎症、肿瘤坏死因子、白介素1、白介素6、白介素8。幽门螺杆菌和脆弱芽孢杆菌都与炎症有关 分别是胃癌和结肠癌。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，这些刺激都会导致SMO增加 表达，过氧化氢的产生，以及可被抑制的SMO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 潜在的致癌DNA损伤。因此，这些数据表明，SMO可能代表着一种新的、至关重要的 重要的化学预防靶点。因此，评估SMO作为化学预防靶点的潜力 治疗我们将：1)定义炎症刺激诱导表达的分子机制 2)单独和联合使用脆性芽孢杆菌APC+/-MinAPC？716小鼠模型 使用SMO和/或SMO基因敲除的抑制剂，以确定细菌炎症之间是否存在直接联系， SMO活性、ROS的产生与肿瘤的发生发展。通过了解所涉及的路径 调节炎症诱导的SMO表达、过氧化氢产生和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.