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

Authors
 Na-Young Song  ;  Feng Zhu  ;  Zining Wang  ;  Jami Willette-Brown  ;  Sichuan Xi  ;  Zhonghe Sun  ;  Ling Su  ;  Xiaolin Wu  ;  Buyong Ma  ;  Ruth Nussinov  ;  Xiaojun Xia  ;  David S. Schrump  ;  Peter F. Johnson  ;  Michael Karin  ;  Yinling Hu 
Citation
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol.115(4) : E812-E821, 2018 
Journal Title
 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 
ISSN
 0027-8424 
Issue Date
2018
Keywords
IKKα ; ROS ; cell senescence ; lung adenocarcinoma ; tumor progression
Abstract
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.
Full Text
https://www.pnas.org/content/115/4/E812.long
DOI
10.1073/pnas.1717520115
Appears in Collections:
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
Yonsei Authors
Song, Na-Young(송나영) ORCID logo https://orcid.org/0000-0001-8658-7049
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/169787
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