The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Loss of Keap1 Function Activates Nrf2 and Provides Advantages for Lung Cancer Cell Growth
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. [Cancer Res 2008;68(5):1303–9]
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Self-citationKobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.16.7130-7139.2004 · Cited by 2,224
Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer
Singh, A., Misra, V., Thimmulappa, R. K., Lee, H., Ames, S., Hoque, M. O., Herman, J. G., Baylin, S. B., Sidransky, D., Gabrielson, E., et al. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030420 · Cited by 1,060
Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer
Padmanabhan, B., Tong, K. I., Ohta, T., Nakamura, Y., Scharlock, M., Ohtsuji, M., Kang, M.-I., Kobayashi, A., Yokoyama, S., & Yamamoto, M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.013 · Cited by 735 · cited 3×
“Collectively, these observations suggest that the Nrf2-Keap1 pathway acts as a double-edged sword: it protects the body from chemical carcinogenesis but aids the growth and development of cancer cells ( 13 ).”
BackgroundInfluentialSelf-citationTwo-site substrate recognition model for the Keap1-Nrf2 system: A hinge and latch mechanism
Tong, K. I., Kobayashi, A., Katsuoka, F., & Yamamoto, M. (2006) · Biological Chemistry · doi:10.1515/bc.2006.164 · Cited by 473
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Cited by
ROS and the DNA damage response in cancer
Srinivas, U. S., Tan, B. W. Q., Vellayappan, B. A., & Jeyasekharan, A. D. (2019) · Redox Biology · doi:10.1016/j.redox.2018.101084 · Cited by 2,144
Nrf2:INrf2 (Keap1) signaling in oxidative stress
Kaspar, J. W., Niture, S. K., & Jaiswal, A. K. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.07.035 · Cited by 1,648
The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway
Baird, L., & Yamamoto, M. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00099-20 · Cited by 1,542
Self-citationMolecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution
Taguchi, K., Motohashi, H., & Yamamoto, M. (2011) · Genes to Cells · doi:10.1111/j.1365-2443.2010.01473.x · Cited by 1,478
Self-citationRole of Glutathione in Cancer Progression and Chemoresistance
Traverso, N., Ricciarelli, R., Nitti, M., Marengo, B., Furfaro, A. L., Pronzato, M. A., Marinari, U. M., & Domenicotti, C. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/972913 · Cited by 1,208
Metadata
- Authors
- 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.
- Venue
- Cancer Research
- Published
- 2008-03-01
- Volume
- 68
- Issue
- 5
- Pages
- 1303-1309
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2129726289
- Cited by
- 629
- References
- 6
- FWCI
- 13.52
- Type
- journal article
- Language
- en
- Open access
- closed
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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. https://doi.org/10.1158/0008-5472.can-07-5003
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