Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors?
Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors?
复制标题
鸟氨酸脱羧酶活性和基因表达的改变是否有助于Cox抑制剂的抗增殖特性？
DOI：
10.1038/sj.bjc.6600815
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发表时间：
2003-04-07
影响因子：
8.8
通讯作者：
Bartnik, W
中科院分区：
文献类型：
--
作者：
Ostrowski, J;Wocial, T;Skurzak, H;Bartnik, W
环氧化酶（考克斯）的两种异构体参与生长控制;考克斯-1在大多数细胞中组成性表达，而考克斯-2是响应细胞刺激的诱导酶。在肿瘤组织中发现的考克斯-2的诱导导致细胞生长增加、细胞凋亡抑制、血管生成激活和免疫应答降低。尽管考克斯-1和考克斯-2抑制剂都是细胞增殖的抑制剂，并且似乎是肿瘤发生的化学预防剂，但是考克斯抑制剂介导抗增殖作用的分子机制仍然没有被很好地确定。本研究比较了考克斯-1和考克斯-2抑制剂阿司匹林和塞来昔布对大鼠肝癌HTC-IR细胞的作用。对以下内容进行了评估：细胞增殖和凋亡，鸟氨酸脱羧酶（ODC）活性，以及三种即刻早期基因c-myc、Egr-1和c-fos的模式表达。我们已经证明，在体外用选择性考克斯-2抑制剂塞来昔布处理肝细胞与诱导细胞凋亡和完全抑制细胞增殖有关。阿司匹林表现出一个小的抗增殖作用，与细胞凋亡无关。塞来昔布治疗产生剂量和时间依赖性的ODC活性降低。此外，在较高的药物浓度下，增殖期细胞中ODC活性的下降幅度大于静息期细胞。在阿司匹林处理的细胞中观察到对ODC活性的抑制作用小得多。两种考克斯抑制剂没有改变c-myc的表达，显著降低Egr-1的表达，差异改变c-fos的表达;阿司匹林没有改变，但塞来昔布显著降低c-fos-mRNA的水平。我们的研究表明，塞来昔布和阿司匹林具有抑制ODC活性和改变即刻早期基因表达模式的能力。似乎观察到的一些效应可能与COX非依赖性途径有关。考克斯抑制剂的确切作用机制应在使用这些药物进行癌症化学预防治疗之前确定。
Two isoforms of cyclooxygenase (COX) participate in growth control; COX-1 is constitutively expressed in most cells, and COX-2 is an inducible enzyme in response to cellular stimuli. An induction of COX-2 found in neoplastic tissues results in increased cell growth, inhibition of apoptosis, activation of angiogenesis, and decreased immune responsiveness. Although both COX-1 and COX-2 inhibitors are suppressors of cell proliferation and appear to be chemopreventive agents for tumorigenesis, the molecular mechanisms mediating antiproliferative effect of COX inhibitors are still not well defined. This study contrasts and compares the effects of aspirin and celecoxib, inhibitors of COX-1 and COX-2, in rat hepatoma HTC-IR cells. The following were assessed: cell proliferation and apoptosis, ornithine decarboxylase (ODC) activity, and pattern expression of three immediate-early genes, c-myc, Egr-1, and c-fos. We have shown that the treatment of hepatocytes in vitro with the selective COX-2 inhibitor, celecoxib, was associated with induction of apoptosis and complete inhibition of cellular proliferation. Aspirin exhibited a small antiproliferative effect that was not associated with apoptosis. Treatment with celecoxib produced dose- and time-dependent decrease in ODC activity. In addition, at higher drug concentration the decrease in ODC activity was greater in proliferating than in resting cells. Much lesser inhibitory effect on ODC activity was observed in aspirin-treated cells. The two COX inhibitors did not change c-myc expression, significantly decreased the expression of Egr-1, and differentially altered expression of c-fos; aspirin did not change, but celecoxib dramatically decreased the levels of c-fos-mRNA. Our study revealed that celecoxib and aspirin share the ability to inhibit ODC activity and alter the pattern of immediate-early gene expression. It seems that some of the observed effects are likely to be related to COX-independent pathways. The precise mechanisms of action of COX inhibitors should be defined before using these drugs for cancer chemopreventive therapy.