Lung cancer is a leading cause of cancer mortality worldwide. We previously demonstrated that IKKα kinase dead knock-in (IkkαK44A/K44A, KA) mice spontaneously develop lung SCCs, which is associated with IKKα reduction and increased inflammation. Currently, lung adenocarcinoma (ADC) has surpassed SCC. Although downregulation of IKKα has been reported in lung ADCs, the role of IKKα is not clarified yet. Here, we attempted to verify whether IKKα inactivation plays a role in development of lung adenocarcinomas (ADCs). K-rasG12D (Kras) mice are a well-established lung ADC model. Thus, we generated K-rasG12D;IkkαK44A/K44A (Kras;KA) and K-rasG12D;Ikkαf/f (Kras;FF) mice and activated oncogenic K-rasG12D with intratracheal injection of adenovirus carrying the cre recombinase gene in these mice. At 4∼4.5 months after treatment, both Kras;KA and Kras;FF mice showed enhanced bronchial hyperproliferation and increased number of lung tumors than Kras mice. The histology showed that lung tumors from both mice can be classified into ADCs, while no SCCs were found in Kras;KA and Kras;FF mice. Finally, Kras;FF mice had shorter life span due to labored breathing than Kras mice. Thus, IKKα plays an important role in lung ADCs as well as SCCs. It is well known that the oncogene activation such as Kras can induce a senescence program to suppress the progression of benign tumors. We found that IKKα loss diminished Kras-induced senescence, given the results from senescence-associated β-gal assay and Ki67 staining. We previously reported that inflammation is required for development of lung SCCs in KA mice. Macrophages were significantly accumulated in the lung of Kras;FF mice as well. In general, inflammation can cause oxidative stress. In line with this notion, the microarray analysis revealed that several antioxidant genes were markedly downregulated, while expression of some reactive oxygen species (ROS)-generating genes was increased in the lung tissues from Kras;FF mice compared to Kras mice. In consistent, IKKα depletion was correlated with increased level of ROS in lung tumors, which resulted in further oxidative DNA damage. Interestingly, tumors from Kras mice also showed IKKα reduction compared to WT lungs. Taken together, these findings suggest that IKKα reduction can promote Kras-driven lung tumorigenesis through its interplay between inflammation and oxidative stress. Inflammation and oxidative stress can sustain and exacerbate each other, leading to a vicious cycle of tumor-prone microenvironment. It is evident that IKKα plays a crucial role in inflammation from massive investigations. The role of IKKα in oxidative stress, however, is not clarified yet. Thus, our investigation of the role of IKKα on lung ADC development in the context of modulating oxidative stress will provide better strategies to break the vicious cycle between inflammation, oxidative stress and lung tumorigenesis and noble therapeutic targets for treatment.

Citation Format: Na-Young Song, Jami Willette-Brown, Mahesh Dalta, Yinling Hu. IKKα at the crossroad between inflammation, oxidative stress and lung carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 801. doi:10.1158/1538-7445.AM2015-801