Carcinogenesis Advance Access originally published online on April 15, 2008
Carcinogenesis 2008 29(6):1235-1243; doi:10.1093/carcin/bgn095
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Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2
Department of Pharmacology and Toxicology
1 Department of Pathology
2 Department of Aerospace and Mechanical Engineering, University of Arizona, Tucson, AZ 85721, USA
* To whom correspondence should be addressed. Tel: +1 520 626 9918; Fax: +1 520 626 2466; Email: dzhang{at}pharmacy.arizona.edu
Drug resistance during chemotherapy is the major obstacle to the successful treatment of many cancers. Here, we report that inhibition of NF-E2-related factor 2 (Nrf2) may be a promising strategy to combat chemoresistance. Nrf2 is a critical transcription factor regulating a cellular protective response that defends cells against toxic insults from a broad spectrum of chemicals. Under normal conditions, the low constitutive amount of Nrf2 protein is maintained by the Kelch-like ECH-associated protein1 (Keap1)-mediated ubiquitination and proteasomal degradation system. Upon activation, this Keap1-dependent Nrf2 degradation mechanism is quickly inactivated, resulting in accumulation and activation of the antioxidant response element (ARE)-dependent cytoprotective genes. Since its discovery, Nrf2 has been viewed as a ‘good’ transcription factor that protects us from many diseases. In this study, we demonstrate the dark side of Nrf2: stable overexpression of Nrf2 resulted in enhanced resistance of cancer cells to chemotherapeutic agents including cisplatin, doxorubicin and etoposide. Inversely, downregulation of the Nrf2-dependent response by overexpression of Keap1 or transient transfection of Nrf2–small interfering RNA (siRNA) rendered cancer cells more susceptible to these drugs. Upregulation of Nrf2 by the small chemical tert-butylhydroquinone (tBHQ) also enhanced the resistance of cancer cells, indicating the feasibility of using small chemical inhibitors of Nrf2 as adjuvants to chemotherapy to increase the efficacy of chemotherapeutic agents. Furthermore, we provide evidence that the strategy of using Nrf2 inhibitors to increase efficacy of chemotherapeutic agents is not limited to certain cancer types or anticancer drugs and thus can be applied during the course of chemotherapy to treat many cancer types.
Abbreviations: ARE, antioxidant response element; CBD, chitin-binding domain; cDNA, complementary DNA; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HA, hemagglutinin; HO-1, heme oxygenase-1; Keap1, Kelch-like ECH-associated protein1; mRNA, messenger RNA; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; Nrf2, NF-E2-related factor 2; NQO1, NAD(P)H quinone oxidoreductase 1; PCR, polymerase chain reaction; shRNA, short hairpin RNA; siRNA, small interfering RNA; tBHQ, tert-butylhydroquinone
These authors contributed equally to this work. Received January 16, 2008; revised April 6, 2008; accepted April 7, 2008.