Loss of Keap1 Function Activates Nrf2 and Provides Advantages for Lung Cancer Cell Growth

DOI PDF PubMed 被引用文献55件 オープンアクセス
  • Tsutomu Ohta
    1Center for Medical Genomics,
  • Kumiko Iijima
    1Center for Medical Genomics,
  • Mamiko Miyamoto
    1Center for Medical Genomics,
  • Izumi Nakahara
    1Center for Medical Genomics,
  • Hiroshi Tanaka
    5Department of Computational Biology, Tokyo Medical and Dental University, Tokyo, Japan;
  • Makiko Ohtsuji
    6Center for Tsukuba Advanced Research Alliance and Japan Science and Technology Agency-Exploratory Research for Advanced Technology Environmental Response Project, University of Tsukuba, Tsukuba, Japan; and
  • Takafumi Suzuki
    6Center for Tsukuba Advanced Research Alliance and Japan Science and Technology Agency-Exploratory Research for Advanced Technology Environmental Response Project, University of Tsukuba, Tsukuba, Japan; and
  • Akira Kobayashi
    6Center for Tsukuba Advanced Research Alliance and Japan Science and Technology Agency-Exploratory Research for Advanced Technology Environmental Response Project, University of Tsukuba, Tsukuba, Japan; and
  • Jun Yokota
    2Biology Division,
  • Tokuki Sakiyama
    1Center for Medical Genomics,
  • Tatsuhiro Shibata
    3Pathology Division, and
  • Masayuki Yamamoto
    6Center for Tsukuba Advanced Research Alliance and Japan Science and Technology Agency-Exploratory Research for Advanced Technology Environmental Response Project, University of Tsukuba, Tsukuba, Japan; and
  • Setsuo Hirohashi
    3Pathology Division, and

書誌事項

公開日
2008-03-01
DOI
  • 10.1158/0008-5472.can-07-5003
公開者
American Association for Cancer Research (AACR)

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説明

<jats:title>Abstract</jats:title> <jats:p>Oxidative and electrophilic stresses are sensed by Keap1, which activates Nrf2 to achieve cytoprotection by regulating the expression of drug-metabolizing and antioxidative stress enzymes/proteins. Because oxidative and electrophilic stresses cause many diseases, including cancer, we hypothesized that an abnormality in the Nrf2-Keap1 system may facilitate the growth of cancer cells. We sequenced the KEAP1 gene of 65 Japanese patients with lung cancer and identified five nonsynonymous somatic mutations at a frequency of 8%. We also identified two nonsynonymous somatic KEAP1 gene mutations and two lung cancer cell lines expressing KEAP1 at reduced levels. In lung cancer cells, low Keap1 activity (due to mutations or low-level expression) led to nuclear localization and constitutive activation of Nrf2. The latter resulted in constitutive expression of cytoprotective genes encoding multidrug resistance pumps, phase II detoxifying enzymes, and antioxidative stress enzymes/proteins. Up-regulation of these target genes in lung cancer cells led to cisplatin resistance. Nrf2 activation also stimulated growth of lung cancer–derived cell lines expressing KEAP1 at low levels and in mutant cell lines and in Keap1-null mouse embryonic fibroblasts under homeostatic conditions. Thus, inhibition of NRF2 may provide new therapeutic approaches in lung cancers with activation of Nrf2. [Cancer Res 2008;68(5):1303–9]</jats:p>

収録刊行物

  • Cancer Research

    Cancer Research 68 (5), 1303-1309, 2008-03-01

    American Association for Cancer Research (AACR)

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