RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy.
Nuclear factor erythroid-2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of electrophile and xenobiotic detoxification enzymes and efflux proteins, which confer cytoprotection against oxidative stress and apoptosis in normal cells. Loss of function mutations in the Nrf2 inhibitor, Kelch-like ECH-associated protein (Keap1), results in constitutive activation of Nrf2 function in non-small cell lung cancer. In this study, we show that constitutive activation of Nrf2 in lung cancer cells promotes tumorigenicity and contributes to chemoresistance by up-regulation of glutathione, thioredoxin, and the drug efflux pathways involved in detoxification of electrophiles and broad spectrum of drugs. RNAi-mediated reduction of Nrf2 expression in lung cancer cells induces generation of reactive oxygen species, suppresses tumor growth, and results in increased sensitivity to chemotherapeutic drug-induced cell death in vitro and in vivo. Inhibiting Nrf2 expression using naked siRNA duplexes in combination with carboplatin significantly inhibits tumor growth in a subcutaneous model of lung cancer. Thus, targeting Nrf2 activity in lung cancers, particularly those with Keap1 mutations, could be a promising strategy to inhibit tumor growth and circumvent chemoresistance.
Singh
Anju
A
Department of Environmental Health Sciences, Division of Toxicology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Boldin-Adamsky
Swetlana
S
Thimmulappa
Rajesh K
RK
Rath
Srikanta K
SK
Ashush
Hagit
H
Coulter
Jonathan
J
Blackford
Amanda
A
Goodman
Steven N
SN
Bunz
Fred
F
Watson
Walter H
WH
Gabrielson
Edward
E
Feinstein
Elena
E
Biswal
Shyam
S
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000072019:Kelch-Like ECH-Associated Protein 1; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000502:physiology; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000494:pharmacology*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; D034741:RNA, Small Interfering