Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth

Tsutomu Ohta, Kumiko Iijima, Mamiko Miyamoto, Izumi Nakahara, Hiroshi Tanaka, Makiko Ohtsuji, Takafumi Suzuki, Akira Kobayashi, Jun Yokota, Tokuki Sakiyama, Tatsuhiro Shibata, Masayuki Yamamoto, Setsuo Hirohashi

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412 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1303-1309
Number of pages7
JournalCancer Research
Volume68
Issue number5
DOIs
Publication statusPublished - 2008 Mar 1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Ohta, T., Iijima, K., Miyamoto, M., Nakahara, I., Tanaka, H., Ohtsuji, M., Suzuki, T., Kobayashi, A., Yokota, J., Sakiyama, T., Shibata, T., Yamamoto, M., & Hirohashi, S. (2008). Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Research, 68(5), 1303-1309. https://doi.org/10.1158/0008-5472.CAN-07-5003