Celecoxib induces proliferation and Amphiregulin production in colon subepithelial myofibroblasts, activating erk1-2 signaling in synergy with EGFR
Celecoxib induces proliferation and Amphiregulin production in colon subepithelial myofibroblasts, activating erk1-2 signaling in synergy with EGFR
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DOI：
10.1016/j.canlet.2012.09.008
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发表时间：
2013-01-01
期刊：
影响因子：
9.7
通讯作者：
Ferrari, Nicoletta
中科院分区：
文献类型：
--
作者：
Benelli, Roberto;Vene, Roberta;Ferrari, Nicoletta
考克斯-2抑制剂塞来昔布，在III期临床试验中用于预防散发性结肠腺瘤，减少了新腺瘤的出现，但不能影响结肠癌的发病率。此外，5年随访显示，与安慰剂组相比，停止塞来昔布治疗的患者腺瘤发生率增加。在APC（min/+）小鼠模型中，塞来昔布短期治疗可减少肠道腺瘤，但长期给药可诱导成纤维细胞活化和肠道纤维化，最终增加肿瘤负荷。塞来昔布直接激活人结肠肌成纤维细胞（MF）的途径尚未研究，我们发现MF可被无毒剂量的塞来昔布激活。塞来昔布在5 '端诱导erk 1 -2和Akt磷酸化。这种短期激活显然不足以引起表型变化，但EGFR的当代触发引起了令人印象深刻的协同效应，诱导MF增殖和双调蛋白（AREG）的新表达和释放，双调蛋白是一种参与结肠癌进展的众所周知的EGFR激动剂。作为对这些观察结果的证实，erk抑制剂U 0126和EGFR抑制剂Tyrphostin和Cetuximab能够对比AREG诱导。我们的数据提供了塞来昔布直接激活MF赋予EGFR信号传导的证据。根据这些结果，与EGFR（或erk 1 -2）抑制剂的联合可以消除塞来昔布的脱靶活性，可能扩展该药物预防结肠癌的潜力。(C)2012爱思唯尔爱尔兰有限公司保留所有权利。
The COX-2 inhibitor Celecoxib, tested in phase III trials for the prevention of sporadic colon adenomas, reduced the appearance of new adenomas, but was unable to affect the incidence of colon cancer. Moreover the 5 years follow-up showed that patients discontinuing Celecoxib treatment had an increased incidence of adenomas as compared to the placebo arm. In the APC(min/+) mouse model short term treatment with Celecoxib reduced gut adenomas, but a prolonged administration of the drug induced fibroblast activation and intestinal fibrosis with a final tumor burden. The way Celecoxib could directly activate human colon myofibroblasts (MF) has not yet been investigated.We found that MF are activated by non toxic doses of Celecoxib. Celecoxib induces erk1-2 and Akt phosphorylation within 5'. This short term activation is apparently insufficient to cause phenotypic changes, but the contemporary triggering of EGFR causes an impressive synergic effect inducing MF proliferation and the neo-expression and release of Amphiregulin (AREG), a well known EGFR agonist involved in colon cancer progression. As a confirm to these observations, the erk inhibitor U0126 and the EGFR inhibitors Tyrphostin and Cetuximab were able to contrast AREG induction.Our data provide evidence that Celecoxib directly activates MF empowering EGFR signaling. According to these results the association with EGFR (or erk1-2) inhibitors could abolish the off-target activity of Celecoxib, possibly extending the potential of this drug for colon cancer prevention. (C) 2012 Elsevier Ireland Ltd. All rights reserved.