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

¹ Center for Medical Genomics, ² Biology Division, ³ Pathology Division, and ⁴ Cancer Genomics Project, National Cancer Center Research Institute; ⁵ Department of Computational Biology, Tokyo Medical and Dental University, Tokyo, Japan; ⁶ Center 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 ⁷ Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan

Requests for reprints: Tsutomu Ohta, Center for Medical Genomics, National Cancer Center Research Institute, 5-1-1 Tsukiji Chuo-ku, Tokyo 104-0045, Japan. Phone: 81-3-3542-2511; Fax: 81-3-3248-1631; E-mail: cota{at}gan2.res.ncc.go.jp.

Key Words: KEAP1 • NRF2 • lung cancer • cell growth • cytoprotective genes

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]