Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. IκB kinase α (IKKα) has been shown to suppress lung SCC development, but its role in ADC is unknown. We found inactivating mutations and homologous or hemizygous deletions in the CHUK locus, which encodes IKKα, in human lung ADCs. The CHUK deletions significantly reduced the survival time of patients with lung ADCs harboring KRAS mutations. In mice, lung-specific Ikkα ablation (IkkαΔLu) induces spontaneous ADCs and promotes KrasG12D -initiated ADC development, accompanied by increased cell proliferation, decreased cell senescence, and reactive oxygen species (ROS) accumulation. IKKα deletion up-regulates NOX2 and down-regulates NRF2, leading to ROS accumulation and blockade of cell senescence induction, which together accelerate ADC development. Pharmacologic inhibition of NADPH oxidase or ROS impairs KrasG12D-mediated ADC development in IkkαΔLu mice. Therefore, IKKα modulates lung ADC development by controlling redox regulatory pathways. This study demonstrates that IKKα functions as a suppressor of lung ADC in human and mice through a unique mechanism that regulates tumor cell-associated ROS metabolism.
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 2018 Jan 23|
Bibliographical noteFunding Information:
Cancer Center, Guangzhou, China. All human samples used in this study were approved by the National Institutes of Health Internal Review Board (protocol 06-C-0014) and by the Ethics Committee and Institutional Review Board of Sun Yat-Sen University Cancer Center (YB2017-023), and informed consent was been obtained from all patients.
aCancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702; bState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China; cThoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892; dLaboratory of Molecular Technology, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702; eCancer and Inflammation Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702; fMouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702; and gDepartment of Pharmacology, University of California, San Diego, La Jolla, CA 92093
ACKNOWLEDGMENTS. This work was supported by the National Cancer Institute (Grants ZIA BC011212 and ZIA BC 011391, to Y.H.), the Frederick National Laboratory for Cancer Research, National Institutes of Health (NIH) (Contract HHSN261200800001E, to R.N.), and the Intramural Research Program of the National Cancer Institute’s Center for Cancer Research (P.F.J.). Work in the M.K. laboratory is supported through the National Institute for Environmental Health Studies Superfund Research Program (Grant P42ES010337), and the NIH (Grants R01 A1043477 and R01 CA163798), and work in the X.X. laboratory is supported by the National Natural Science Foundation of China (Grant 81472578) and Guangdong Esophageal Cancer Center (Grant M201607).
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