Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth.
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.
Ohta
Tsutomu
T
Center for Medical Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan. cota@gan2.res.ncc.go.jp
Iijima
Kumiko
K
Miyamoto
Mamiko
M
Nakahara
Izumi
I
Tanaka
Hiroshi
H
Ohtsuji
Makiko
M
Suzuki
Takafumi
T
Kobayashi
Akira
A
Yokota
Jun
J
Sakiyama
Tokuki
T
Shibata
Tatsuhiro
T
Yamamoto
Masayuki
M
Hirohashi
Setsuo
S
D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D000072019:Kelch-Like ECH-Associated Protein 1; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress
D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human