Selective Cox-2 inhibitor celecoxib induces epithelial-mesenchymal transition in human lung cancer cells via activating MEK-ERK signaling
Selective Cox-2 inhibitor celecoxib induces epithelial-mesenchymal transition in human lung cancer cells via activating MEK-ERK signaling
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DOI：
10.1093/carcin/bgs367
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发表时间：
2013-03-01
期刊：
影响因子：
4.7
通讯作者：
Qu, Jie-ming
中科院分区：
文献类型：
--
作者：
Wang, Zi-li;Fan, Zhi-qiang;Qu, Jie-ming
越来越多的证据表明环氧化酶2（考克斯2）的高表达与非小细胞肺癌（NSCLC）的恶性程度有关，这为应用考克斯2抑制剂作为NSCLC的辅助治疗提供了理论依据。然而，在临床试验中，选择性考克斯-2抑制剂塞来昔布（celecoxib）加入化疗未能使NSCLC患者的生存获益，这促使研究重新评估NSCLC治疗的这一策略。在这项研究中，我们观察到，无论考克斯-2状态如何，临床相关浓度的塞来昔布治疗均可诱导NSCLC细胞的上皮-间充质转化（EMT），然而，使用另一种考克斯-2抑制剂依托度酸无法重现。塞来昔布刺激的EMT反过来促进细胞侵袭并使细胞对化疗产生抗性。通过使用特异性抑制剂或RNA干扰破坏信号通路完整性的进一步机制研究表明，塞来昔布诱导的NSCLC细胞EMT是转化生长因子-1/Smad信号传导不可或缺的。相反，活化的MEK/ERK/SNAIL 1信号转导主要解释了塞来昔布诱导的EMT。综上所述，我们的研究揭示了考克斯-2抑制剂对NSCLC细胞EMT的不同影响，与考克斯-2抑制无关，其中塞来昔布治疗通过EMT诱导导致转移和耐药性。这些发现揭示了在NSCLC治疗的临床试验中应用考克斯-2抑制剂，特别是塞来昔布会增加癌症转移和化疗耐药性的风险，并敦促在进行临床应用之前进行密集的临床前评估。
Increasing evidence has suggested that high expression level of cyclooxygenase-2 (Cox-2) is associated with the malignancies of nonsmall cell lung cancer (NSCLC), leading to a rationale of applying Cox-2 inhibitors as adjuvant therapy in the treatment of NSCLC. However, the addition of celecoxib, a selective Cox-2 inhibitor, to chemotherapy in clinical trials failed to benefit the survival of NSCLC patients, which urges the investigation to re-evaluate this strategy for NSCLC treatment. In this study, we observed that celecoxib treatment at clinically relevant concentrations induced epithelial-mesenchymal transition (EMT) in NSCLC cells regardless of Cox-2 status, which, however, was not recapitulated using another Cox-2 inhibitor, etodolac. Celecoxib-stimulated EMT in turn promoted cell invasion and rendered cells resistant to chemotherapy. Further mechanistic investigation by disrupting the integrity of signaling pathways using specific inhibitors or RNA interference revealed that celecoxib-induced EMT in NSCLC cells is indispensable of transforming growth factor-1/Smad signaling. Instead, the activated MEK/ERK/SNAIL1 signaling largely accounted for celecoxib-induced EMT. Taken together, our study reveals the diverse impacts of Cox-2 inhibitors on EMT in NSCLC cells independent of Cox-2 inhibition, where celecoxib treatment leads to metastasis and chemoresistance via EMT induction. These findings reveal the increased risks of cancer metastasis and chemoresistance by applying Cox-2 inhibitors, celecoxib in particular, in clinical trials of NSCLC treatment and urge intensive preclinical assessment before proceeding to clinical application.