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PMID: 18413364 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Carcinogenesis ·Vol. 29 ·No. 6 ·2008-06-00 ·Pages 1235-43

Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, Chen W, Yi X, Zheng W, Wondrak GT, Wong PK, Zhang DD

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.

MeSH Terms
Antineoplastic Agents/pharmacology Cell Line, Tumor Drug Resistance, Neoplasm/physiology Gene Expression Humans Immunoblotting Intracellular Signaling Peptides and Proteins/metabolism Kelch-Like ECH-Associated Protein 1 NF-E2-Related Factor 2/metabolism Neoplasms/metabolism RNA, Messenger/analysis RNA, Small Interfering Reverse Transcriptase Polymerase Chain Reaction Transfection
Chemicals
Antineoplastic Agents Intracellular Signaling Peptides and Proteins KEAP1 protein, human Kelch-Like ECH-Associated Protein 1 NF-E2-Related Factor 2 NFE2L2 protein, human RNA, Messenger RNA, Small Interfering
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Wang Xiao-Jun
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.
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 D
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Article Info
Journal
Carcinogenesis
Abbr.
Carcinogenesis
ISSN
1460-2180
DOI
10.1093/carcin/bgn095
Published
2008-06-00
Epub
2008-00-15
Pages
1235-43
Language
English
Region
England
NLM ID
8008055
PMCID
PMC3312612
Subset
IM
Grants
NIEHS NIH HHS · P30 ES006694 · United States
NIEHS NIH HHS · R01 ES015010 · United States
NIEHS NIH HHS · T32 ES007091 · United States
NIEHS NIH HHS · ES015010-01 · United States
External Links
PubMed source DOI: 10.1093/carcin/bgn095 PMC Full Text View journal details
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