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

Xiao Jun Wang, Zheng Sun, Nicole F. Villeneuve, Shirley Zhang, Fei Zhao, Yanjie Li, Weimin Chen, Xiaofang Yi, Wenxin - Zheng, Georg T Wondrak, Pak Kin Wong, Donna Zhang

Research output: Contribution to journalArticle

437 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1235-1243
Number of pages9
JournalCarcinogenesis
Volume29
Issue number6
DOIs
StatePublished - Jun 2008

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NF-E2-Related Factor 2
Pharmaceutical Preparations
Neoplasms
Transcription Factors
Antioxidant Response Elements
Drug Therapy
Poisons
Ubiquitination
Etoposide
Adjuvant Chemotherapy
Drug Resistance
Doxorubicin
Small Interfering RNA
Cisplatin

ASJC Scopus subject areas

  • Cancer Research

Cite this

Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. / Wang, Xiao Jun; Sun, Zheng; Villeneuve, Nicole F.; Zhang, Shirley; Zhao, Fei; Li, Yanjie; Chen, Weimin; Yi, Xiaofang; Zheng, Wenxin -; Wondrak, Georg T; Wong, Pak Kin; Zhang, Donna.

In: Carcinogenesis, Vol. 29, No. 6, 06.2008, p. 1235-1243.

Research output: Contribution to journalArticle

Wang, Xiao Jun ; Sun, Zheng ; Villeneuve, Nicole F. ; Zhang, Shirley ; Zhao, Fei ; Li, Yanjie ; Chen, Weimin ; Yi, Xiaofang ; Zheng, Wenxin - ; Wondrak, Georg T ; Wong, Pak Kin ; Zhang, Donna. / Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. In: Carcinogenesis. 2008 ; Vol. 29, No. 6. pp. 1235-1243.
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AB - 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.

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