COX-2 inhibitors suppress lung cancer cell growth by inducing p21 via COX-2 independent signals
COX-2 inhibitors suppress lung cancer cell growth by inducing p21 via COX-2 independent signals
复制标题
DOI：
10.1016/j.lungcan.2005.10.015
复制
发表时间：
2006-03-01
期刊：
影响因子：
5.3
通讯作者：
Roman, J
中科院分区：
文献类型：
--
作者：
Han, SW;Roman, J
考克斯-2参与控制人非小细胞肺癌（NSCLC）细胞生长。考克斯-2发挥其促有丝分裂作用的机制尚未完全阐明，但已提出刺激前列腺素E2的产生和改变细胞周期蛋白依赖性激酶抑制剂p21（WAF-1/CIP 1/MDA-6）（p2 i）的表达。在此，我们证明两种考克斯-2抑制剂（NS 398和尼美舒利）抑制NSCLC细胞增殖并诱导凋亡，这些作用与诱导p21 mRNA和蛋白表达有关。然而，考克斯-2抑制剂的抗生长作用和它们诱导p21的能力不受考克斯-2 siRNA的影响，表明它们的作用不依赖于考克斯-2。相反，MEK-1/Erk通路的激活是必需的，因为考克斯-2抑制剂刺激ERK的磷酸化，并且它们的作用被该通路的抑制剂PD 98095阻断。此外，我们表明，NS 398和尼美舒利诱导p21基因启动子活性，这是由PD 98095阻止。考克斯-2抑制剂增加了核蛋白与p21基因启动子区Spl位点的结合。与p21的作用一致，我们发现p21反义寡核苷酸阻止了考克斯-2抑制剂对细胞生长的影响。总之，我们的研究结果表明，考克斯-2抑制剂通过MEK-1/ERK信号传导和涉及Spl的DNA-蛋白质相互作用诱导p21基因表达来抑制NSCLC细胞生长。这些发现揭示了考克斯-2抑制剂在肺癌细胞生长中对p21基因调控的机制，该途径代表了潜在的治疗靶点。(c)2005 Elsevier爱尔兰有限公司ALL。rights reserved.
COX-2 has been implicated in the control of human non-small cell Lung carcinoma (NSCLC) cell growth. The mechanisms by which COX-2 exerts its mitogenic effects have not been entirely elucidated, but stimulation of prostaglandin E2 production and alterations in the expression of the cyclin-dependent kinase inhibitor p21(WAF-1/CIP1/MDA-6)(p2i) have been suggested. Here, we demonstrate that two COX-2 inhibitors (NS398 and Nimesulide) inhibit proliferation and induce apoptosis in NSCLC cells, and these effects were associated with induction of p21 mRNA and protein expression. However, the anti-growth effect of the COX-2 inhibitors and their ability to induce p21 were not affected by COX-2 siRNA suggesting that their actions were COX-2 independent. Instead, activation of the MEK-1/Erk pathway was necessary since COX-2 inhibitors stimulated the phosphorylation of ERKs, and their effects were blocked by PD98095, an inhibitor of this pathway. Furthermore, we show that both NS398 and Nimesulide induced p21 gene promoter activity and this was prevented by PD98095. COX-2 inhibitors increased nuclear protein binding to the Spl site in the promoter region of the p21 gene. Consistent with a rote for p21, we found that p21 antisense oligonucleotides prevented the effects of COX-2 inhibitors on cell growth. In summary, our results suggest that COX-2 inhibitors suppress NSCLC cell growth by inducing the expression of the p21 gene through MEK-1/ERK signaling and DNA-protein interactions involving Spl. These observations unveil a mechanism for p21 gene regulation by COX-2 inhibitors in lung carcinoma cell growth and this pathway represents a potential target for therapy. (c) 2005 Elsevier Ireland Ltd. ALL. rights reserved.