title: Auranofin, an inhibitor of thioredoxin reductase, induces apoptosis in hepatocellular carcinoma Hep3B cells by generation of reactive oxygen species.
abstract: Mammalian thioredoxin reductase (TrxR) plays a vital role in restoring cellular redox balance disrupted by reactive oxygen species (ROS) generation and oxidative damage. Here, we evaluated whether auranofin, a selective inhibitor of TrxR, could serve as a potential anti-cancer agent through its selective targeting of TrxR activity in Hep3B hepatocellular carcinoma cells. Auranofin treatment reduced the TrxR activity of these cells and induced apoptosis, which were accompanied by up-regulation of death receptors (DRs) and activation of caspases, as well as promotion of proteolytic degradation of poly(ADP-ribose)-polymerase. Treatment with a pan-caspase inhibitor reversed the auranofin-induced apoptosis and growth suppression, indicating that auranofin may induce apoptosis through a caspase-dependent mechanism involving both the intrinsic and extrinsic apoptotic pathways. Auranofin also significantly altered mitochondrial function, promoting mitochondrial membrane permeabilization and cytochrome c release by regulating Bcl-2 family proteins; these events were accompanied by an accumulation of ROS. Inhibition of ROS generation with the ROS quencher significantly attenuated the inactivation of TrxR in auranofin-treated cells and almost completely suppressed the auranofin-induced up-regulation of DRs and activation of caspases, thereby preventing auranofin-induced apoptosis and loss of cell viability. Taken together, these findings indicate that auranofin inhibition of TrxR activity in Hep3B cells activates ROS- and caspase-dependent apoptotic signaling pathways and triggers cancer cell death.
authors.affiliation: Department of Biochemistry, Dongeui University College of Korean Medicine, Busan 614-052, Republic of Korea.choiyh@deu.ac.kr.
authors.forename: Hyun
authors.initials: H
authors.lastname: Hwang-Bo
authors.forename: Jin-Woo
authors.initials: JW
authors.lastname: Jeong
authors.forename: Min Ho
authors.initials: MH
authors.lastname: Han
authors.forename: Cheol
authors.initials: C
authors.lastname: Park
authors.forename: Su-Hyun
authors.initials: SH
authors.lastname: Hong
authors.forename: Gi-Young
authors.initials: GY
authors.lastname: Kim
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Moon
authors.forename: Jaehun
authors.initials: J
authors.lastname: Cheong
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Young Hyun
authors.initials: YH
authors.lastname: Yoo
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001310:Auranofin / Q000008:administration & dosage*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D017382:Reactive Oxygen Species; D001310:Auranofin; D013880:Thioredoxin-Disulfide Reductase