title: Caspase-3 activation as a key factor for HBx-transformed cell death.
abstract: OBJECTIVE
  Nuclear factor-kappa B (NF-kappaB) activation has been associated with the tumorigenic growth of hepatitis B virus X protein (HBx)-transformed cells. This study was aimed to find a key target for treatment of HBx-mediated cancers.
  
  
  METHODS
  NF-kappaB activation, endoplasmic reticulum-stress (ER-stress), caspase-3 activation, and cell proliferation were evaluated after Chang/HBx cells permanently expressing HBx viral protein were treated with inhibitors of NF-kappaB, proteasome and DNA topoisomerase.
  
  
  RESULTS
  Inhibition of NF-kappaB transcriptional activity by transient transfection with mutant plasmids encoding Akt1 and glycogen synthase kinase-3beta (GSK-3beta), or by treatment with chemical inhibitors, wortmannin and LY294002, showed little effect on the survival of Chang/HBx cells. Furthermore, IkappaBalpha (S32/36A) mutant plasmid or other NF-kappaB inhibitors, 1-pyrrolidinecarbonidithioic acid and sulphasalazine, were also shown to have little effect on the cell proliferation. By contrast, proteasome inhibitor-1 (Pro1) and MG132 enhanced the HBx-induced ER-stress response and the subsequent activation of caspase-12, -9 and -3 and reduced cell proliferation. Camptothecin (CPT), however, triggered activation of caspase-3 without induction of caspase-12, and reduced cell proliferation. In addition, CPT-induced cell death was reversed by pre-treatment with z-DEVD, a caspase-3-specific inhibitor.
  
  
  CONCLUSIONS
  Detailed exploitation of the regulators of caspase-3 activation could open the gate for finding an efficient target for development of anticancer therapeutics against HBx-transformed hepatocellular carcinoma.
authors.affiliation: Functional Metabolomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Yuseong, South Korea.
authors.forename: A
authors.initials: A
authors.lastname: Kim
authors.forename: O S
authors.initials: OS
authors.lastname: Kwon
authors.forename: S O
authors.initials: SO
authors.lastname: Kim
authors.forename: L
authors.initials: L
authors.lastname: He
authors.forename: E Y
authors.initials: EY
authors.lastname: Bae
authors.forename: M S
authors.initials: MS
authors.lastname: Lee
authors.forename: S J
authors.initials: SJ
authors.lastname: Jeong
authors.forename: J H
authors.initials: JH
authors.lastname: Shim
authors.forename: D Y
authors.initials: DY
authors.lastname: Yoon
authors.forename: C H
authors.initials: CH
authors.lastname: Kim
authors.forename: A
authors.initials: A
authors.lastname: Moon
authors.forename: K E
authors.initials: KE
authors.lastname: Kim
authors.forename: J S
authors.initials: JS
authors.lastname: Ahn
authors.forename: B Y
authors.initials: BY
authors.lastname: Kim
mesh_terms: D002166:Camptothecin / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002461:Cell Line, Transformed; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D007976:Leupeptins; D016328:NF-kappa B; D009842:Oligopeptides; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C090535:benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal; C057628:hepatitis B virus X protein; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D002166:Camptothecin