title: Bufotalin sensitizes death receptor-induced apoptosis via Bid- and STAT1-dependent             pathways.
abstract: Tumor necrosis factor-alpha (TNF-α) and TNF-related apoptosis-inducing ligand             (TRAIL) are apoptosis-inducing ligands that stimulate death receptors. In this             study, we investigated the effects of bufotalin, a major compound in toad venom,             on sensitizing TNF-α and TRAIL-induced apoptosis of HeLa cells. Bufotalin promoted             death receptor-mediated cell death, especially TRAIL-induced apoptosis, through             activation of caspase-3 and PARP-1. Mitochondrial Bid-dependent pathway was activated             in TNF-α-induced cell death. Cotreatment of bufotalin with TRAIL resulted in the             downregulation of anti-apoptotic proteins, including Bcl-XL, Mcl-1, survivin and             XIAP, and the up-regulation of MAPKs and TRAIL receptor DR5. In addition, phosphorylation             of STAT1 was strongly inhibited by bufotalin. Moreover, DR5 expression was induced             by knocking down the STAT1 expression. Moreover, the TRAIL-induced apoptotic response             was promoted by STAT1 siRNA. Our results demonstrated that bufotalin is a powerful             sensitizer of death receptor-induced apoptosis in cancer cells.
authors: Division of Pathogenic Biochemistry, Institute of Natural Medicine,                     University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors: Pornthip
authors: P
authors: Waiwut
authors: Akiko
authors: A
authors: Inujima
authors: Hiroki
authors: H
authors: Inoue
authors: Ikuo
authors: I
authors: Saiki
authors: Hiroaki
authors: H
authors: Sakurai
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism*; D002018:Bufanolides / Q000494:pharmacology*; D004357:Drug Synergism; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis* / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002018:Bufanolides; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C004600:bufotalin