Inhibition of COX-2 with NS-398 decreases colon cancer cell motility through blocking epidermal growth factor receptor transactivation: possibilities for combination therapy
Inhibition of COX-2 with NS-398 decreases colon cancer cell motility through blocking epidermal growth factor receptor transactivation: possibilities for combination therapy
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DOI：
10.1111/j.1365-2184.2007.00459.x
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发表时间：
2007-10-01
影响因子：
8.5
通讯作者：
Pignatelli, M.
中科院分区：
文献类型：
--
作者：
Banu, N.;Buda, A.;Pignatelli, M.
尽管非类固醇抗炎药物的确切作用机制尚不清楚，但其在预防和治疗结直肠癌方面的应用已被证明是非常有兴趣的。环氧合酶-2(COX-2)的过度表达和随后前列腺素的产生促进了肿瘤的转移，并在体外被证明增加了细胞的运动性。目的：探讨NS-398对COX-2的特异性抑制作用(NS-398是COX-2的选择性抑制剂)是否能够抑制结直肠癌细胞的运动能力，以及这种作用是否通过表皮生长因子受体(EGFR)的反式激活来调节。材料和方法：采用Transwell滤过法测定细胞的运动能力。用Western印迹分析和逆转录聚合酶链式反应检测COX-2、EGFR磷酸化和前列腺素E-2(PGE(2))受体的表达。用酶免疫法测定NS-398处理后的PGE(2)浓度。结果：NS-398可显著降低HT29和HCA7结直肠癌细胞株的PGE(2)水平，减少细胞迁移，PGE(2)的作用可被逆转。此外，NS-398特异性抑制COX-2降低了结直肠癌细胞中EGFR的磷酸化。用AG1478直接抑制EGFR活性可减少PGE(2)刺激的运动，清楚地表明PGE(2)通过EGFR信号通路发挥作用。NS-398和AG1478的新组合显著减少了结直肠癌细胞的迁移。结论：NS-398用于结直肠癌的化学预防和辅助治疗可能部分是通过抑制细胞运动起作用的。此外，我们的数据表明，非类固醇抗炎药与EGFR拮抗剂的联合应用可以进一步探索未来的临床应用。
The use of non-steroidal anti-inflammatory drugs has proved of great interest in the prevention and treatment of colorectal cancer, although their precise mechanisms of action remain unclear. Overexpression of cyclooxygenase-2 (COX-2) and subsequent prostaglandin production promote metastasis and have been shown to increase cell motility in vitro. Objective: We have aimed to elucidate whether specific inhibition of COX-2 with NS-398 (NS-398 is a selective inhibitor of COX-2) would be able to inhibit motility of colorectal cancer cells and whether this was modulated through epidermal growth factor receptor (EGFR) transactivation. Materials and Methods: A transwell filter assay was used to study cell motility. Expression of COX-2, EGFR phosphorylation and prostaglandin E-2 (PGE(2)) receptors were assessed by Western blot analysis and reverse transcriptase-polymerase chain reaction. PGE(2) concentrations after NS-398 treatment were estimated by enzyme immunoassay. Results: Treatment with NS-398 significantly reduced PGE(2) levels and reduced cell migration in the HT29 and HCA7 colorectal carcinoma cell lines and this effect was rescued by addition of PGE(2). Furthermore, specific inhibition of COX-2 with NS-398 reduced EGFR phosphorylation in colorectal cancer cells. Direct inhibition of EGFR activity with AG1478 reduced PGE(2)-stimulated motility, clearly demonstrating that PGE(2) acts via the EGFR-signalling pathway. The novel combination of NS-398 and AG1478 dramatically reduced migration of colorectal cancer cells. Conclusion: The data presented indicate that the use of NS-398 in chemoprevention and adjuvant therapy for colorectal cancer may work in part, through the inhibition of cell motility. Furthermore, our data suggest that the combined use of non-steroidal anti-inflammatory drugs with EGFR antagonists could be explored further for future use in the clinic.