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Carcinogenesis Advance Access published online on April 15, 2008
Carcinogenesis, doi:10.1093/carcin/bgn095
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2

Xiao-Jun Wang1,^, Zheng Sun1,^, Nicole F. Villeneuve1, Shirley Zhang1, Fei Zhao1, Yanjie Li1, Weimin Chen1, Xiaofang Yi2, Wenxin Zheng2, Georg T. Wondrak1, Pak Kin Wong3 and Donna D. Zhang1,*

1 Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721
2 Department of Pathology, University of Arizona, Tucson, Arizona 85721
3 Aerospace & Mechanical Engineering Department, Tucson, Arizona 85721

* Address correspondence to: Donna D. Zhang, Department of Pharmacology and Toxicology, University of Arizona, 1703 E. Mabel St., Tucson, Arizona 85721. Tel: 520-626-9918; fax: 520-626-2466; E-mail: 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 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 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 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, down-regulation of the Nrf2-dependent response by overexpression of Keap1 or transient-transfection of Nrf2-siRNA rendered cancer cells more susceptible to these drugs. Upregulation of Nrf2 by the small chemical 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 anti-cancer drugs, thus can be applied during the course of chemotherapy to treat many cancer types.

Key Words: Nrf2 • Keap1 • chemotherapeutic • cisplatin • doxorubicin • etoposide • chemoresistance

{wedge} These two authors contributed equally.

Received January 16, 2008; revised April 6, 2008; accepted April 7, 2008.


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