The DOI matches its Crossref record; 8 of the 8 references it cites were found in a registry or an index.
RNAi -Mediated Silencing of Nuclear Factor Erythroid-2–Related Factor 2 Gene Expression in Non–Small Cell Lung Cancer Inhibits Tumor Growth and Increases Efficacy of Chemotherapy
Open accessAbstract
Nuclear factor erythroid-2–related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of electrophile and xenobiotic detoxification enzymes and efflux proteins, which confer cytoprotection against oxidative stress and apoptosis in normal cells. Loss of function mutations in the Nrf2 inhibitor, Kelch-like ECH-associated protein (Keap1), results in constitutive activation of Nrf2 function in non–small cell lung cancer. In this study, we show that constitutive activation of Nrf2 in lung cancer cells promotes tumorigenicity and contributes to chemoresistance by up-regulation of glutathione, thioredoxin, and the drug efflux pathways involved in detoxification of electrophiles and broad spectrum of drugs. RNAi-mediated reduction of Nrf2 expression in lung cancer cells induces generation of reactive oxygen species, suppresses tumor growth, and results in increased sensitivity to chemotherapeutic drug–induced cell death in vitro and in vivo. Inhibiting Nrf2 expression using naked siRNA duplexes in combination with carboplatin significantly inhibits tumor growth in a subcutaneous model of lung cancer. Thus, targeting Nrf2 activity in lung cancers, particularly those with Keap1 mutations, could be a promising strategy to inhibit tumor growth and circumvent chemoresistance. [Cancer Res 2008;68(19):7975–84]
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Citations
Cites
Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141046 · Cited by 3,630
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
Selective Modification of Glutathione Metabolism
Meister, A. (1983) · Science · doi:10.1126/science.6836290 · Cited by 1,267 · cited 2×
“Since Meister (32) claimed that the cellular metabolism of glutathione could affect the fate of chemotherapeutic agents, several reports have shown that glutathione content is increased in Cancer Res 2008; 68: (19).”
BackgroundTrachootham, D., Zhou, Y., Zhang, H., Demizu, Y., Chen, Z., Pelicano, H., Chiao, P. J., Achanta, G., Arlinghaus, R. B., Liu, J., et al. (2006) · Cancer Cell · doi:10.1016/j.ccr.2006.08.009 · Cited by 1,080
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
Self-citationStructural 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 1×
“Loss of Keap1 activity leading to constitutive activation of Nrf2 in lung cancer cells up-regulates the expression of antioxidants, electrophile, and drug detoxification enzymes and efflux proteins (21, 22).”
BackgroundDisruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice
Rangasamy, T., Guo, J., Mitzner, W. A., Roman, J., Singh, A., Fryer, A. D., Yamamoto, M., Kensler, T. W., Tuder, R. M., Georas, S. N., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050538 · Cited by 580
Self-citationSmall interfering RNA targeting Fas protects mice against renal ischemia-reperfusion injury
Hamar, P., Song, E., Kökény, G., Chen, A., Ouyang, N., & Lieberman, J. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0406421101 · Cited by 250
Cited by
The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis
Yamamoto, M., Kensler, T. W., & Motohashi, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00023.2017 · Cited by 1,968
Molecular 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
Nrf2 Redirects Glucose and Glutamine into Anabolic Pathways in Metabolic Reprogramming
Mitsuishi, Y., Taguchi, K., Kawatani, Y., Shibata, T., Nukiwa, T., Aburatani, H., Yamamoto, M., & Motohashi, H. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.05.016 · Cited by 1,395
The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer
Kansanen, E., Kuosmanen, S. M., Leinonen, H., & Levonen, A.-L. (2013) · Redox Biology · doi:10.1016/j.redox.2012.10.001 · Cited by 1,313
“In addition, PI3K inhibitors [11,13] and Nrf2 siRNA [14] have been used to inhibit Nrf2 in cancer cells.”
BackgroundNRF2 and cancer: the good, the bad and the importance of context
Sporn, M. B., & Liby, K. T. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3278 · Cited by 1,067
Metadata
- Authors
- Singh, A., Boldin-Adamsky, S., Thimmulappa, R. K., Rath, S. K., Ashush, H., Coulter, J., Blackford, A., Goodman, S. N., Bunz, F., Watson, W. H., Gabrielson, E., Feinstein, E., & Biswal, S.
- Venue
- Cancer Research
- Published
- 2008-09-30
- Volume
- 68
- Issue
- 19
- Pages
- 7975-7984
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W1972439337
- Cited by
- 367
- References
- 8
- FWCI
- 9.06
- Type
- journal article
- Language
- en
- Open access
- green
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- Singh, A., Boldin-Adamsky, S., Thimmulappa, R. K., Rath, S. K., Ashush, H., Coulter, J., Blackford, A., Goodman, S. N., Bunz, F., Watson, W. H., Gabrielson, E., Feinstein, E., & Biswal, S. (2008). RNAi -Mediated Silencing of Nuclear Factor Erythroid-2–Related Factor 2 Gene Expression in Non–Small Cell Lung Cancer Inhibits Tumor Growth and Increases Efficacy of Chemotherapy. Cancer Research. https://doi.org/10.1158/0008-5472.can-08-1401
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