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检验我们最近克隆的精胺氧化酶（SMO）通过细胞内多胺氧化产生活性氧物质在炎症相关肿瘤发生中起重要作用的假设。据估计，20-30%的上皮癌的病因与炎症直接相关。虽然许多炎症细胞，细胞因子和途径已经牵连，连接炎症和必要的致癌DNA突变的分子事件是未知的。我们最近发现的人类SMO可能提供了一个这样的联系。SMO是哺乳动物多胺代谢途径的新成员。其活性产物是多胺、亚精胺、3-氨基丙醛和活性氧H2 O2。我们已经证明，大的，肿瘤特异性的增加精胺氧化酶活性可以导致选择性肿瘤细胞死亡，从而提供了一个有针对性的抗肿瘤治疗的策略。然而，非细胞毒性水平的H2 O2的慢性产生可对正常细胞产生有害影响，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由多种刺激诱导，包括幽门螺杆菌感染、暴露于产肠杆菌性脆弱类杆菌（ETBF）和暴露于一般炎症介质TNF？，IL-1？IL-6和IL 8。两个都是H. pylori和B. fragilis分别与胃癌和结肠癌的炎症相关。TNF的产生、释放和活性？和其它细胞因子是炎症和损伤的常见反应。事实上，这些刺激都导致增加的SMO表达，H2 O2的生产，和可测量的DNA损伤，这是通过抑制SMO阻断，表明ROS产生的多胺分解代谢酶SMO是一个直接的机制连接炎症和潜在的致癌DNA损伤。因此，这些数据表明，SMO可能是一个新的和非常重要的化学预防目标。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）使用B。fragilis APCMinAPC？716小鼠模型，以及与SMO和/或SMO敲除的抑制剂组合，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。通过了解参与调节炎症诱导的SMO表达，H2 O2产生和DNA损伤的途径，并通过定义它们在炎症相关上皮癌的起始和进展中的作用，可能会出现多种化学预防治疗的新靶点。公共卫生相关性：炎症与许多上皮癌的发生相关;然而，这种关联的分子基础尚不清楚。在本申请中提出的结果牵连过氧化氢产生的精胺氧化酶（SMO）在响应TNF？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有助于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.