title: Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2.
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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721, USA.
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Sun
authors.forename: Nicole F
authors.initials: NF
authors.lastname: Villeneuve
authors.forename: Shirley
authors.initials: S
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Zhao
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Li
authors.forename: Weimin
authors.initials: W
authors.lastname: Chen
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Yi
authors.forename: Wenxin
authors.initials: W
authors.lastname: Zheng
authors.forename: Georg T
authors.initials: GT
authors.lastname: Wondrak
authors.forename: Pak Kin
authors.initials: PK
authors.lastname: Wong
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering