Ritesh K Aggarwal, Simone Sidoli, Jingli Wang, Srabani Sahu, Rahul Sanawar, Varun Gupta, Srinivas Aluri, Vineeth Sukrithan, Charan T R Vegivinti, Phaedon D Zavras, Divij Verma, Shanisha Gordon-Mitchell, Beamon Agarwal, Tanya Verma, Daniel T Starczynowski, Ulrich G Steidl, Aditi Shastri, Balazs Halmos, Lindsay M LaFave, Haiying Cheng, Amit Verma, Yiyu Zou
{"title":"Smoking carcinogen induced inflammation promotes lung carcinogenesis via IRAK4 activation.","authors":"Ritesh K Aggarwal, Simone Sidoli, Jingli Wang, Srabani Sahu, Rahul Sanawar, Varun Gupta, Srinivas Aluri, Vineeth Sukrithan, Charan T R Vegivinti, Phaedon D Zavras, Divij Verma, Shanisha Gordon-Mitchell, Beamon Agarwal, Tanya Verma, Daniel T Starczynowski, Ulrich G Steidl, Aditi Shastri, Balazs Halmos, Lindsay M LaFave, Haiying Cheng, Amit Verma, Yiyu Zou","doi":"10.1158/1078-0432.CCR-24-2182","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>Even though smoking is associated with lung cancer, the exact molecular pathways that link carcinogens with inflammation and oncogenic transformation are not well elucidated. Two major carcinogens in cigarette smoke, Nicotine-derived nitrosamine ketone, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(α)pyrene (BaP) have not been tested in models that mimic inhaled exposure for prolonged periods of time.</p><p><strong>Experimental design: </strong>ICR mice were treated with intratracheal delivery of NNK and BaP (NB) for 18 months. Tissue microarrays from human lung cancers were evaluated for IRAK4 expression. Functional effects of IRAK4 inhibition were evaluated in cell lines and in xenografts.</p><p><strong>Results: </strong>Smoking-associated carcinogen treated mice developed epithelial dysplasia followed by lung cancers at increased rates relative to controls. Histology revealed myeloid inflammation in murine lung tissues. Lung macrophages showed elevated levels of pro-inflammatory IL-1b when exposed to cigarette smoking condensate. A key downstream mediator of IL-1β signaling, Interleukin 1 receptor associated kinase-4 (IRAK4), was overexpressed in murine lung tissues exposed to carcinogens. Majority of human lung cancer samples also exhibited overactivated IRAK4 expression. IRAK4 localized in microtubules in lung cancer cell lines. Using mass spectrometry on isolated microtubules, we observed that IRAK4 inhibition was associated with decreased phosphorylation of tubular motility proteins including MYH9. Inhibition of IRAK4 resulted in decreased invasion in lung cancer cell lines and reduced growth of lung cancer xenografts.</p><p><strong>Conclusions: </strong>These data demonstrate that smoking associated carcinogens can be linked to oncogenic transformation via inflammatory IRAK4 activation.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0000,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/1078-0432.CCR-24-2182","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Purpose: Even though smoking is associated with lung cancer, the exact molecular pathways that link carcinogens with inflammation and oncogenic transformation are not well elucidated. Two major carcinogens in cigarette smoke, Nicotine-derived nitrosamine ketone, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo(α)pyrene (BaP) have not been tested in models that mimic inhaled exposure for prolonged periods of time.
Experimental design: ICR mice were treated with intratracheal delivery of NNK and BaP (NB) for 18 months. Tissue microarrays from human lung cancers were evaluated for IRAK4 expression. Functional effects of IRAK4 inhibition were evaluated in cell lines and in xenografts.
Results: Smoking-associated carcinogen treated mice developed epithelial dysplasia followed by lung cancers at increased rates relative to controls. Histology revealed myeloid inflammation in murine lung tissues. Lung macrophages showed elevated levels of pro-inflammatory IL-1b when exposed to cigarette smoking condensate. A key downstream mediator of IL-1β signaling, Interleukin 1 receptor associated kinase-4 (IRAK4), was overexpressed in murine lung tissues exposed to carcinogens. Majority of human lung cancer samples also exhibited overactivated IRAK4 expression. IRAK4 localized in microtubules in lung cancer cell lines. Using mass spectrometry on isolated microtubules, we observed that IRAK4 inhibition was associated with decreased phosphorylation of tubular motility proteins including MYH9. Inhibition of IRAK4 resulted in decreased invasion in lung cancer cell lines and reduced growth of lung cancer xenografts.
Conclusions: These data demonstrate that smoking associated carcinogens can be linked to oncogenic transformation via inflammatory IRAK4 activation.
期刊介绍:
Clinical Cancer Research is a journal focusing on groundbreaking research in cancer, specifically in the areas where the laboratory and the clinic intersect. Our primary interest lies in clinical trials that investigate novel treatments, accompanied by research on pharmacology, molecular alterations, and biomarkers that can predict response or resistance to these treatments. Furthermore, we prioritize laboratory and animal studies that explore new drugs and targeted agents with the potential to advance to clinical trials. We also encourage research on targetable mechanisms of cancer development, progression, and metastasis.