title: Selective Cox-2 inhibitor celecoxib induces epithelial-mesenchymal transition in human lung cancer cells via activating MEK-ERK signaling.
abstract: Increasing evidence has suggested that high expression level of cyclooxygenase-2 (Cox-2) is associated with the malignancies of non-small 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-β1/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.
authors.affiliation: Department of Pulmonary Medicine, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China.
authors.forename: Zi-li
authors.initials: ZL
authors.lastname: Wang
authors.forename: Zhi-qiang
authors.initials: ZQ
authors.lastname: Fan
authors.forename: Han-dong
authors.initials: HD
authors.lastname: Jiang
authors.forename: Jie-ming
authors.initials: JM
authors.lastname: Qu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000068579:Celecoxib; D045744:Cell Line, Tumor / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D004285:Dogs; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D055785:Gene Knockdown Techniques; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D051785:Smad Proteins / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000502:physiology
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D052246:Cyclooxygenase 2 Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D011720:Pyrazoles; D034741:RNA, Small Interfering; D051785:Smad Proteins; D013449:Sulfonamides; D053773:Transforming Growth Factor beta1; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C482128:MAP2K2 protein, human; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human; D000068579:Celecoxib