Celecoxib prevents malignant progression of smoking-induced lung tumors via suppression of the COX-2/PGE2 signaling pathway in mice
IntroductionLung cancer is characterized by a poor prognosis and is a significant comorbidity of chronic obstructive pulmonary disease (COPD). Therefore, effective chemopreventive agents are warranted. We evaluated the effects of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on the prevention of...
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Frontiers Media S.A.
2025-03-01
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| author | Kaori Sakurai Shotaro Chubachi Jun Miyata Junko Hamamoto Tatsuro Naganuma Tatsuro Naganuma Takashi Shimada Shiro Otake Shingo Nakayama Hidehiro Irie Akihiro Tsutsumi Naofumi Kameyama Ahmed E. Hegab Masayuki Shimoda Masayuki Shimoda Hideki Terai Hiroyuki Yasuda Yae Kanai Makoto Arita Makoto Arita Makoto Arita Makoto Arita Koichi Fukunaga |
| author_facet | Kaori Sakurai Shotaro Chubachi Jun Miyata Junko Hamamoto Tatsuro Naganuma Tatsuro Naganuma Takashi Shimada Shiro Otake Shingo Nakayama Hidehiro Irie Akihiro Tsutsumi Naofumi Kameyama Ahmed E. Hegab Masayuki Shimoda Masayuki Shimoda Hideki Terai Hiroyuki Yasuda Yae Kanai Makoto Arita Makoto Arita Makoto Arita Makoto Arita Koichi Fukunaga |
| author_sort | Kaori Sakurai |
| collection | DOAJ |
| description | IntroductionLung cancer is characterized by a poor prognosis and is a significant comorbidity of chronic obstructive pulmonary disease (COPD). Therefore, effective chemopreventive agents are warranted. We evaluated the effects of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on the prevention of lung-carcinoma development using an intermittent smoking-induced lung-carcinoma mouse model. Additionally, we explored COX-2’s role in lipid metabolism.MethodsMale A/J mice were exposed to sham air or mainstream cigarette smoke for 20 weeks. Vehicle or celecoxib was administered via intragastric feeding once daily. Lung tissues were analyzed for tumor nodules and emphysema; the bronchoalveolar lavage fluid was collected for cell counting. COX-2 expression was measured using real-time polymerase chain reaction and western blotting; lipidomic analysis was conducted using liquid chromatography-tandem mass spectrometry. Cell proliferation and colony-forming assays were performed on LA-4 cells to assess the effects of prostaglandins and COX-2 inhibitors.ResultsIntermittent smoking exposure increased lung adenomas, adenocarcinomas, and COX-2 expression. Lung adenomas were characterized by abundant COX-2-positive cells. Celecoxib reduced intermittent smoking-induced inflammation, emphysema, and cell counts in the bronchoalveolar lavage fluid and decreased the incidence of lung adenocarcinomas, whereas the total number of observed lung tumors was unchanged. Celecoxib markedly suppressed single-smoke-induced prostaglandin E2 (PGE2) production in the airway. PGE2 increased LA-4 cell viability via the EP4 receptor and promoted colony formation.DiscussionCelecoxib effectively inhibited lung-carcinoma development, inflammation, and emphysema, demonstrating the potential for chemoprevention in smokers and patients with COPD. Further studies on EP4 inhibitors for the prevention of emphysema and lung cancer are warranted. |
| format | Article |
| id | doaj-art-a49fa70d1daf464aad0c4bb7d54d3316 |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-03-01 |
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| spelling | doaj-art-a49fa70d1daf464aad0c4bb7d54d33162025-08-20T02:50:30ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-03-011610.3389/fimmu.2025.15577901557790Celecoxib prevents malignant progression of smoking-induced lung tumors via suppression of the COX-2/PGE2 signaling pathway in miceKaori Sakurai0Shotaro Chubachi1Jun Miyata2Junko Hamamoto3Tatsuro Naganuma4Tatsuro Naganuma5Takashi Shimada6Shiro Otake7Shingo Nakayama8Hidehiro Irie9Akihiro Tsutsumi10Naofumi Kameyama11Ahmed E. Hegab12Masayuki Shimoda13Masayuki Shimoda14Hideki Terai15Hiroyuki Yasuda16Yae Kanai17Makoto Arita18Makoto Arita19Makoto Arita20Makoto Arita21Koichi Fukunaga22Division of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, JapanDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, JapanDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, JapanDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, JapanDivision of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, JapanLaboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, JapanDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, JapanDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, JapanDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, JapanDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, JapanDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, JapanDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, JapanMedical Education Center, School of Medicine, International University of Health and Welfare, Narita, JapanDepartment of Pathology, Keio University School of Medicine, Tokyo, JapanDepartment of Pathology, The Jikei University School of Medicine, Tokyo, JapanDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, JapanDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, JapanDepartment of Pathology, Keio University School of Medicine, Tokyo, JapanDivision of Physiological Chemistry and Metabolism, Graduate School of Pharmaceutical Sciences, Keio University, Tokyo, JapanLaboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, JapanCellular and Molecular Epigenetics Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, JapanHuman Biology-Microbiome-Quantum Research Center (WPI-Bio2Q), Keio University, Tokyo, JapanDivision of Pulmonary Medicine, Department of Internal Medicine, Keio University School of Medicine, Tokyo, JapanIntroductionLung cancer is characterized by a poor prognosis and is a significant comorbidity of chronic obstructive pulmonary disease (COPD). Therefore, effective chemopreventive agents are warranted. We evaluated the effects of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on the prevention of lung-carcinoma development using an intermittent smoking-induced lung-carcinoma mouse model. Additionally, we explored COX-2’s role in lipid metabolism.MethodsMale A/J mice were exposed to sham air or mainstream cigarette smoke for 20 weeks. Vehicle or celecoxib was administered via intragastric feeding once daily. Lung tissues were analyzed for tumor nodules and emphysema; the bronchoalveolar lavage fluid was collected for cell counting. COX-2 expression was measured using real-time polymerase chain reaction and western blotting; lipidomic analysis was conducted using liquid chromatography-tandem mass spectrometry. Cell proliferation and colony-forming assays were performed on LA-4 cells to assess the effects of prostaglandins and COX-2 inhibitors.ResultsIntermittent smoking exposure increased lung adenomas, adenocarcinomas, and COX-2 expression. Lung adenomas were characterized by abundant COX-2-positive cells. Celecoxib reduced intermittent smoking-induced inflammation, emphysema, and cell counts in the bronchoalveolar lavage fluid and decreased the incidence of lung adenocarcinomas, whereas the total number of observed lung tumors was unchanged. Celecoxib markedly suppressed single-smoke-induced prostaglandin E2 (PGE2) production in the airway. PGE2 increased LA-4 cell viability via the EP4 receptor and promoted colony formation.DiscussionCelecoxib effectively inhibited lung-carcinoma development, inflammation, and emphysema, demonstrating the potential for chemoprevention in smokers and patients with COPD. Further studies on EP4 inhibitors for the prevention of emphysema and lung cancer are warranted.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1557790/fullchronic obstructive pulmonary diseaselung neoplasmscyclooxygenase 2 inhibitorsmokingprostaglandin E2chemoprevention |
| spellingShingle | Kaori Sakurai Shotaro Chubachi Jun Miyata Junko Hamamoto Tatsuro Naganuma Tatsuro Naganuma Takashi Shimada Shiro Otake Shingo Nakayama Hidehiro Irie Akihiro Tsutsumi Naofumi Kameyama Ahmed E. Hegab Masayuki Shimoda Masayuki Shimoda Hideki Terai Hiroyuki Yasuda Yae Kanai Makoto Arita Makoto Arita Makoto Arita Makoto Arita Koichi Fukunaga Celecoxib prevents malignant progression of smoking-induced lung tumors via suppression of the COX-2/PGE2 signaling pathway in mice Frontiers in Immunology chronic obstructive pulmonary disease lung neoplasms cyclooxygenase 2 inhibitor smoking prostaglandin E2 chemoprevention |
| title | Celecoxib prevents malignant progression of smoking-induced lung tumors via suppression of the COX-2/PGE2 signaling pathway in mice |
| title_full | Celecoxib prevents malignant progression of smoking-induced lung tumors via suppression of the COX-2/PGE2 signaling pathway in mice |
| title_fullStr | Celecoxib prevents malignant progression of smoking-induced lung tumors via suppression of the COX-2/PGE2 signaling pathway in mice |
| title_full_unstemmed | Celecoxib prevents malignant progression of smoking-induced lung tumors via suppression of the COX-2/PGE2 signaling pathway in mice |
| title_short | Celecoxib prevents malignant progression of smoking-induced lung tumors via suppression of the COX-2/PGE2 signaling pathway in mice |
| title_sort | celecoxib prevents malignant progression of smoking induced lung tumors via suppression of the cox 2 pge2 signaling pathway in mice |
| topic | chronic obstructive pulmonary disease lung neoplasms cyclooxygenase 2 inhibitor smoking prostaglandin E2 chemoprevention |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1557790/full |
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