Abstract
Nrf2 is a key transcription factor, which induces a cytoprotective gene array. Nrf2 is regulated at the posttranslational level through proteasomal degradation through an interaction with the adapter protein Keap1. High levels of Nrf2, resulting from a loss of function mutation in Keap1, were reported in chemoresistant non-small cell lung cancer. We observed very low levels of Nrf2 and of Nrf2-regulated detoxification proteins as a frequent phenotype in the more chemosensitive breast cancer, and when engineering increased Nrf2 levels, we found resistance to both doxorubicin and paclitaxel. We here show that basal Nrf2 levels in different cell lines correlate with their respective sensitivity to a common cytotoxic chemotherapy. Nrf2 and its regulated genes and proteins are the targets of a major strategy in cancer prevention. Molecules that interfere with the Nrf2–Keap1–Cul3 protein–protein interactions result in higher levels of Nrf2. Both naturally occurring and synthetic molecules with this effect have been suggested as clinical chemopreventive agents, including molecules derived from cruciferous vegetables such as the isothiocyanate sulforaphane and even green tea polyphenols. Here, we determine the impact of these putative chemopreventive agents on the sensitivity of established cancer cell lines to chemotherapy. We confirmed that these molecules do increase Nrf2 and detoxification enzyme levels in breast cancer cell lines with very low basal Nrf2 levels, and this is associated with significant chemoresistance to cytotoxic drugs. Both effects are less in another breast cancer cell line with intermediate Nrf2, and in lung cancer cells with high Nrf2, these same molecules have no effect on Nrf2 but do actually enhance chemoresitance. While the details of dose and schedule of these agents require further study in in vivo models, these data sound a cautionary note for the use of these agents in patients with established cancers who are undergoing chemotherapy treatment.
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Acknowledgments
We wish to thank Drs. Mark Hannink and Moulay Alaoui-Jamali for insightful discussions; Dr. Voker Blank for providing recombinant Nrf2 reagents; Dr. Lesley Alpert for providing clinical breast cancer specimens; Dr. John D. Haynes for providing the antibodies against GSTA1/2, GSTP1, γGCS and NQO1; Dr. Andrew Stolz for providing the antibody against the AKR1C. This work was supported by the grants from the Canadian Institute of Health Research, the Cancer Research Society and a US army breast cancer research concept award (BC033714), and the Fonds de la recherche en santé du Québec.
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Hu, L., Miao, W., Loignon, M. et al. Putative chemopreventive molecules can increase Nrf2-regulated cell defense in some human cancer cell lines, resulting in resistance to common cytotoxic therapies. Cancer Chemother Pharmacol 66, 467–474 (2010). https://doi.org/10.1007/s00280-009-1182-7
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DOI: https://doi.org/10.1007/s00280-009-1182-7