Smoking-Associated Carcinogen-Induced Inflammation Promotes Lung Carcinogenesis via IRAK4 Activation.

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: Mouse models were used for intratracheal delivery of NNK and BaP (NB) for 18 months. Tissue microarrays from human lung cancers were evaluated for IL-1 receptor-associated kinase-4 (IRAK4) expression. Functional effects of IRAK4 inhibition were evaluated in cell lines and 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 proinflammatory IL-1β when exposed to cigarette smoking condensate. A key downstream mediator of IL-1β signaling, IRAK4, was overexpressed in murine lung tissues exposed to carcinogens. The 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 myosin heavy-chain 9. 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.