title: Nrf2 Expression and Apoptosis in Quercetin-treated Malignant Mesothelioma Cells.
abstract: NF-E2-related factor 2 (Nrf2), a basic leucine zipper transcription factor, has recently received a great deal of attention as an important molecule that enhances antioxidative defenses and induces resistance to chemotherapy or radiotherapy. In this study, we investigated the apoptosis-inducing and Nrf2-upregulating effects of quercetin on malignant mesothelioma (MM) MSTO-211H and H2452 cells. Quercetin treatment inhibited cell growth and led to upregulation of Nrf2 at both the mRNA and protein levels without altering the ubiquitination and extending the half-life of the Nrf2 protein. Following treatment with quercetin, analyses of the nuclear level of Nrf2, Nrf2 antioxidant response element-binding assay, Nrf2 promoter-luc assay, and RT-PCR toward the Nrf2-regulated gene, heme oxygenase-1, demonstrated that the induced Nrf2 is transcriptionally active. Knockdown of Nrf2 expression with siRNA enhanced cytotoxicity due to the induction of apoptosis, as evidenced by an increase in the level of proapoptotic Bax, a decrease in the level of antiapoptotic Bcl-2 with enhanced cleavage of caspase-3 and PARP proteins, the appearance of a sub-G0/G1 peak in the flow cytometric assay, and increased percentage of apoptotic propensities in the annexin V binding assay. Effective reversal of apoptosis was observed following pretreatment with the pan-caspase inhibitor Z-VAD. Moreover, Nrf2 knockdown exhibited increased sensitivity to the anticancer drug, cisplatin, presumably by potentiating the oxidative stress induced by cisplatin. Collectively, our data demonstrate the importance of Nrf2 in cytoprotection, survival, and drug resistance with implications for the potential significance of targeting Nrf2 as a promising strategy for overcoming resistance to chemotherapeutics in MM.
authors.affiliation: Division of Molecular Cancer Research, Soonchunhyang Medical Research Institute, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.|Soonchunhyung Environmental Health Center for Asbestos, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.
authors.forename: Yoon-Jin
authors.initials: YJ
authors.lastname: Lee
authors.affiliation: Cell Biology and Genetics in Biological Sciences, College of Computer, Mathematical, and Natural Sciences, University of Maryland, College Park, MD, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Lee
authors.affiliation: Soonchunhyung Environmental Health Center for Asbestos, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.|SDepartment of Biochemistry, College of Medicine, Soonchunhyang University, Cheonan, Korea.
authors.forename: Sang-Han
authors.initials: SH
authors.lastname: Lee
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D011794:Quercetin
keywords: Nrf2; apoptosis; chemoresistance; cisplatin; mesothelioma; quercetin