环氧化酶/脂氧化酶分流降低了环氧化酶-2 抑制在结直肠癌细胞中的抗癌作用。
Cyclooxygenase/lipoxygenase shunting lowers the anti-cancer effect of cyclooxygenase-2 inhibition in colorectal cancer cells.
机构信息
Division of Surgery and Interventional Science, University College London, Rowland Hill Street, London NW3 2PF, UK.
出版信息
World J Surg Oncol. 2012 Sep 26;10:200. doi: 10.1186/1477-7819-10-200.
BACKGROUND
Arachidonic acid metabolite, generated by cyclooxygenase (COX), is implicated in the colorectal cancer (CRC) pathogenesis. Inhibiting COX may therefore have anti-carcinogenic effects. Results from use of non-steroidal anti-inflammatory drugs inhibiting only COX have been conflicting. It has been postulated that this might result from the shunting of arachidonic acid metabolism to the 5-lipoxygenase (5-LOX) pathway. Cancer cell viability is promoted by 5-LOX through several mechanisms that are similar to those of cyclooxygenase-2 (COX-2). Expression of 5-LOX is upregulated in colorectal adenoma and cancer. The aim of this study was to investigate the shunting of arachidonic acid metabolism to the 5-LOX pathway by cyclooxygenase inhibition and to determine if this process antagonizes the anti-cancer effect in colorectal cancer cells.
METHODS
Three colorectal cancer cell lines (HCA7, HT-29 & LoVo) expressing 5-LOX and different levels of COX-2 expression were used. The effects of aspirin (a non-selective COX inhibitor) and rofecoxib (COX-2 selective) on prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) secretion were quantified by ELISA. Proliferation and viability were studied by quantifying double-stranded DNA (dsDNA) content and metabolic activity. Apoptosis was determined by annexin V and propidium iodide staining using confocal microscopy, and caspase-3/7 activity by fluorescent substrate assay.
RESULTS
COX inhibitors suppressed PGE2 production but enhanced LTB4 secretion in COX-2 expressing cell lines (P <0.001). The level of COX-2 expression in colorectal cancer cells did not significantly influence the anti-proliferative and pro-apoptotic effects of COX inhibitors due to the shunting mechanism.
CONCLUSIONS
This study provides evidence of shunting between COX and 5-LOX pathways in the presence of unilateral inhibition, and may explain the conflicting anti-carcinogenic effects reported with use of COX inhibitors.
背景
环氧化酶（COX）生成的花生四烯酸代谢物与结直肠癌（CRC）的发病机制有关。因此，抑制 COX 可能具有抗癌作用。仅抑制 COX 的非甾体抗炎药的使用结果存在冲突。据推测，这可能是由于花生四烯酸代谢转向 5-脂氧合酶（5-LOX）途径所致。5-LOX 通过几种与环氧化酶-2（COX-2）相似的机制促进癌细胞活力。5-LOX 在结直肠腺瘤和癌症中的表达上调。本研究旨在研究 COX 抑制对花生四烯酸代谢向 5-LOX 途径的分流，并确定该过程是否拮抗结直肠癌细胞的抗癌作用。
方法
使用表达 5-LOX 和不同 COX-2 表达水平的三种结直肠癌细胞系（HCA7、HT-29 和 LoVo）。通过 ELISA 定量测定阿司匹林（非选择性 COX 抑制剂）和罗非昔布（COX-2 选择性）对前列腺素 E2（PGE2）和白三烯 B4（LTB4）分泌的影响。通过定量双链 DNA（dsDNA）含量和代谢活性研究增殖和活力。通过使用荧光显微镜进行 Annexin V 和碘化丙啶染色确定细胞凋亡，通过荧光底物测定法测定半胱天冬酶-3/7 活性。
结果
COX 抑制剂抑制 COX-2 表达细胞系中 PGE2 的产生，但增强 LTB4 的分泌（P<0.001）。由于分流机制，结直肠癌细胞中 COX-2 的表达水平并没有显著影响 COX 抑制剂的抗增殖和促凋亡作用。
结论
本研究提供了在单侧抑制存在时 COX 和 5-LOX 途径之间分流的证据，这可能解释了使用 COX 抑制剂报告的相互矛盾的抗癌作用。
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