title: NAD(P)H:Quinone Oxidoreductase-1 Expression Sensitizes Malignant Melanoma Cells to the HSP90 Inhibitor 17-AAG.
abstract: The KEAP1-NRF2 pathway regulates cellular redox homeostasis by transcriptional induction of genes associated with antioxidant synthesis and detoxification in response to oxidative stress. Previously, we reported that KEAP1 mutation elicits constitutive NRF2 activation and resistance to cisplatin (CDDP) and dacarbazine (DTIC) in human melanomas. The present study was conducted to clarify whether an HSP90 inhibitor, 17-AAG, efficiently eliminates melanoma with KEAP1 mutation, as the NRF2 target gene, NQO1, is a key enzyme in 17-AAG bioactivation. In melanoma and non-small cell lung carcinoma cell lines with or without KEAP1 mutations, NQO1 expression and 17-AAG sensitivity are inversely correlated. NQO1 is highly expressed in normal melanocytes and in several melanoma cell lines despite the presence of wild-type KEAP1, and the NQO1 expression is dependent on NRF2 activation. Because either CDDP or DTIC produces reactive oxygen species that activate NRF2, we determined whether these agents would sensitize NQO1-low melanoma cells to 17-AAG. Synergistic cytotoxicity of the 17-AAG and CDDP combination was detected in four out of five NQO1-low cell lines, but not in the cell line with KEAP1 mutation. These data indicate that 17-AAG could be a potential chemotherapeutic agent for melanoma with KEAP1 mutation or NQO1 expression.
authors.affiliation: Department of Tumor Biology, Institute of Biomedical Science, Iwate Medical University, Iwate, Japan.
authors.forename: Shuya
authors.initials: S
authors.lastname: Kasai
authors.affiliation: Department of Tumor Biology, Institute of Biomedical Science, Iwate Medical University, Iwate, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Arakawa
authors.affiliation: Department of Tumor Biology, Institute of Biomedical Science, Iwate Medical University, Iwate, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Okubo
authors.affiliation: Department of Tumor Biology, Institute of Biomedical Science, Iwate Medical University, Iwate, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shigeeda
authors.affiliation: Department of Tumor Biology, Institute of Biomedical Science, Iwate Medical University, Iwate, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Yasuhira
authors.affiliation: Department of Pathology, School of Medicine, Iwate Medical University, Iwate, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Masuda
authors.affiliation: Department of Dermatology, Iwate Medical University, Iwate, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Akasaka
authors.affiliation: Department of Tumor Biology, Institute of Biomedical Science, Iwate Medical University, Iwate, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Shibazaki
authors.affiliation: Department of Tumor Biology, Institute of Biomedical Science, Iwate Medical University, Iwate, Japan.
authors.forename: Chihaya
authors.initials: C
authors.lastname: Maesawa
mesh_terms: D016227:Benzoquinones / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004357:Drug Synergism; D005786:Gene Expression Regulation; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000072019:Kelch-Like ECH-Associated Protein 1; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology; D008544:Melanocytes / Q000201:enzymology; D008545:Melanoma / Q000201:enzymology / Q000473:pathology*; D009154:Mutation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D047029:Lactams, Macrocyclic; C112765:tanespimycin; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D002945:Cisplatin