Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis
Polyamine catabolism contributes to enterotoxigenic Bacteroides fragilis-induced colon tumorigenesis
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DOI：
10.1073/pnas.1010203108
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发表时间：
2011-09-13
影响因子：
11.1
通讯作者：
Casero, Robert A., Jr.
中科院分区：
文献类型：
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作者：
Goodwin, Andrew C.;Shields, Christina E. Destefano;Casero, Robert A., Jr.
据估计，20-30%的上皮癌的病因与炎症直接相关，尽管连接炎症和癌发生的直接分子事件定义不清。在胃肠道疾病的背景下，产肠杆菌性脆弱拟杆菌（ETBF）是慢性炎症的重要来源，并被认为是结直肠癌的风险因素。精胺氧化酶（SMO）是一种多胺分解代谢酶，其可被炎症刺激高度诱导，导致活性氧（ROS）增加和DNA损伤。我们现在证明纯化的B.脆壁毒素（BFT）上调HT 29/c1和T84结肠上皮细胞中的SMO，导致SMO依赖性的ROS产生和γ-H2 A.x（DNA损伤的标志物）的诱导。此外，C57 BL/6小鼠中ETBF诱导的结肠炎与SMO表达增加相关，并且用多胺催化剂N-1，N-4 -双（2，3-丁二烯基）-1，4-丁二胺（MDL 72527）抑制剂治疗小鼠显著降低ETBF诱导的慢性炎症和增殖。最重要的是，在多发性肠肿瘤（Min）小鼠模型中，用MDL 72527治疗使ETBF诱导的结肠肿瘤发生减少69%（P < 0.001）。这些研究的结果表明，SMO是细菌诱导的ROS的来源，与肿瘤发生直接相关，可以作为一个独特的化学预防的目标。
It is estimated that the etiology of 20-30% of epithelial cancers is directly associated with inflammation, although the direct molecular events linking inflammation and carcinogenesis are poorly defined. In the context of gastrointestinal disease, the bacterium enterotoxigenic Bacteroides fragilis (ETBF) is a significant source of chronic inflammation and has been implicated as a risk factor for colorectal cancer. Spermine oxidase (SMO) is a polyamine catabolic enzyme that is highly inducible by inflammatory stimuli resulting in increased reactive oxygen species (ROS) and DNA damage. We now demonstrate that purified B. fragilis toxin (BFT) up-regulates SMO in HT29/c1 and T84 colonic epithelial cells, resulting in SMO-dependent generation of ROS and induction of gamma-H2A.x, a marker of DNA damage. Further, ETBF-induced colitis in C57BL/6 mice is associated with increased SMO expression and treatment of mice with an inhibitor of polyamine catabolism, N-1 ,N-4 -bis(2,3-butandienyl)-1,4-butanediamine (MDL 72527), significantly reduces ETBF-induced chronic inflammation and proliferation. Most importantly, in the multiple intestinal neoplasia (Min) mouse model, treatment with MDL 72527 reduces ETBF-induced colon tumorigenesis by 69% (P < 0.001). The results of these studies indicate that SMO is a source of bacteria-induced ROS directly associated with tumorigenesis and could serve as a unique target for chemoprevention.