title: A diterpenoid derivate compound targets selenocysteine of thioredoxin reductases and induces Bax/Bak-independent apoptosis.
abstract: We have previously shown that the natural diterpenoid derivative S3 induced Bim upregulation and apoptosis in a Bax/Bak-independent manner. However, the exact molecular target(s) of S3 and the mechanism controlling Bim upregulation are still not clear. Here, we identify that S3 targets the selenoproteins TrxR1 and TrxR2 at the selenocysteine residue of the reactive center of the enzymes and inhibits their antioxidant activities. Consequently, cellular ROS is elevated, leading to the activation of FOXO3a, which contributes to Bim upregulation in Bax/Bak-deficient cells. Moreover, S3 retards tumor growth in subcutaneous xenograft tumors by inhibiting TrxR activity in vivo. Our studies delineate the signaling pathway controlling Bim upregulation, which results in Bax/Bak-independent apoptosis and provide evidence that the compounds can act as anticancer agents based on mammalian TrxRs inhibition.
authors.affiliation: Tianjin Key Laboratory of Protein Science, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Liu
authors.forename: Chenglong
authors.initials: C
authors.lastname: Mu
authors.forename: Wen
authors.initials: W
authors.lastname: Yue
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Biao
authors.initials: B
authors.lastname: Ma
authors.forename: Lixia
authors.initials: L
authors.lastname: Zhao
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Quan
authors.initials: Q
authors.lastname: Chen
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
authors.forename: Haiyang
authors.initials: H
authors.lastname: Liu
authors.forename: Xiaojiang
authors.initials: X
authors.lastname: Hao
authors.forename: Yushan
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020134:Catalytic Domain / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D005347:Fibroblasts / Q000166:cytology; D045325:HCT116 Cells; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D017279:Selenocysteine / Q000737:chemistry / Q000378:metabolism*; D051140:Selenoproteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D054481:Thioredoxin Reductase 1 / Q000378:metabolism; D054482:Thioredoxin Reductase 2 / Q000378:metabolism; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D013879:Thioredoxins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D017382:Reactive Oxygen Species; D051140:Selenoproteins; D017279:Selenocysteine; D013879:Thioredoxins; C516124:TXNRD1 protein, human; C516127:TXNRD2 protein, human; D054481:Thioredoxin Reductase 1; D054482:Thioredoxin Reductase 2; D013880:Thioredoxin-Disulfide Reductase
keywords: 15-oxospiramilactone; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; AP1; ASK1; Apoptosis; Bim; CBB; Cancer; Coomassie brilliant blue; DMEM; DNCB; DTNB; Dulbecco's modified Eagle's medium; GRs; HIF-1α; MEF; MTT; N-acetyl-l-cysteine; NAC; NF-κB; PI; ROS; S3; Sec; Thioredoxin reductase; Trx; TrxR; activator protein-1; apoptosis signal-regulating kinase 1; dinitrochlorobenzene; dithiobisnitrobenzoic acid; glutathione reductases; hypoxia-inducible factor 1α; mouse embryonic fibroblast; nuclear transcription factor κ; propidium iodide; reactive oxygen species; selenocysteine; thioredoxin; thioredoxin reductase