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IKKa inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways

  1. Author:
    Song, Na-Young
    Zhu, Feng
    Wang, Zining
    Willette Brown, Jami
    Xi, Sichuan
    Sun, David
    Su, Ling
    Wu, Xiaolin
    Ma, Buyong
    Nussinov, Ruth
    Xia, Xiaojun
    Schrump, David S
    Johnson, Peter
    Karin, Michael
    Hu, Yinling [ORCID]

  2. Author Address

    Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702., State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China., Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892., Laboratory of Molecular Technology, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702., Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD 21702., Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702., Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093 Karinoffice@UCSD.edu huy2@mail.nih.gov., Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702; Karinoffice@UCSD.edu huy2@mail.nih.gov.,
    1. Year: 2018
    2. Date: Jan 23
    3. Epub Date: 2018 01 08
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 115
    2. 4
    3. Pages: E812-E821
  4. Type of Article: Article
  5. ISSN: 0027-8424
  1. Abstract:

    Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. I?B kinase a (IKKa) 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 IKKa, in human lung ADCs. The CHUK deletions significantly reduced the survival time of patients with lung ADCs harboring KRAS mutations. In mice, lung-specific Ikka ablation (Ikka?Lu ) induces spontaneous ADCs and promotes KrasG12D-initiated ADC development, accompanied by increased cell proliferation, decreased cell senescence, and reactive oxygen species (ROS) accumulation. IKKa 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 Ikka?Lu mice. Therefore, IKKa modulates lung ADC development by controlling redox regulatory pathways. This study demonstrates that IKKa functions as a suppressor of lung ADC in human and mice through a unique mechanism that regulates tumor cell-associated ROS metabolism. Copyright © 2018 the Author(s). Published by PNAS.

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External Sources

  1. View Full Text
  2. DOI: 10.1073/pnas.1717520115
  3. PMID: 29311298
  4. View record in Web of Science®
  5. WOS: 000423097800031
  6. PII : 1717520115

Library Notes

  1. Fiscal Year: FY2017-2018
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