title: Role of the eIF4E binding protein 4E-BP1 in regulation of the sensitivity of human pancreatic cancer cells to TRAIL and celastrol-induced apoptosis.
abstract: BACKGROUND
  Tumour cells can be induced to undergo apoptosis after treatment with the tumour necrosis factor α-related death-inducing ligand (TRAIL). Although human pancreatic cancer cells show varying degrees of response they can be sensitised to the pro-apoptotic effects of TRAIL in the presence of celastrol, a natural compound extracted from the plant Tripterygium wilfordii Hook F. One important aspect of the cellular response to TRAIL is the control of protein synthesis, a key regulator of which is the eukaryotic initiation factor 4E-binding protein, 4E-BP1.
  
  
  RESULTS
  We examined the effects of celastrol and TRAIL in several pancreatic cancer cell lines. In cells that are normally resistant to TRAIL, synergistic effects of TRAIL plus celastrol on commitment to apoptosis and inhibition of protein synthesis were observed. These were associated with a strong up-regulation and dephosphorylation of 4E-BP1. The enhancement of 4E-BP1 expression, which correlated with a threefold increase in the level of the 4E-BP1 transcript, was blocked by inhibitors of reactive oxygen species and the JNK protein kinase. When the expression of 4E-BP1 was reduced by an inducible micro-RNA, TRAIL-mediated apoptosis was inhibited.
  
  
  CONCLUSIONS
  These results suggest that 4E-BP1 plays a critical role in the mechanism by which TRAIL and celastrol together cause apoptotic cell death in human pancreatic tumour cells.
authors.affiliation: Translational Control Group, Division of Biomedical Sciences, St George's, University of London, London, SW17 0RE, UK.
authors.forename: Reka
authors.initials: R
authors.lastname: Chakravarthy
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Clemens
authors.forename: Grisha
authors.initials: G
authors.lastname: Pirianov
authors.forename: Nectarios
authors.initials: N
authors.lastname: Perdios
authors.forename: Satvinder
authors.initials: S
authors.lastname: Mudan
authors.forename: Judith E
authors.initials: JE
authors.lastname: Cartwright
authors.forename: Androulla
authors.initials: A
authors.lastname: Elia
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053978:Pentacyclic Triterpenes; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D053978:Pentacyclic Triterpenes; D010750:Phosphoproteins; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014315:Triterpenes; C050414:celastrol
keywords: anti-cancer; protein synthesis; therapeutic; triterpene; tumour necrosis factor α-related apoptosis-inducing ligand (TRAIL)