title: TRAIL-induced expression of uPA and IL-8 strongly enhanced by overexpression of TRAF2 and Bcl-xL in pancreatic ductal adenocarcinoma cells.
abstract: BACKGROUND
  The death ligand, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), induces apoptosis and non-apoptotic signaling in some tumor cells. The purpose of this study was to investigate the roles of the pro-apoptotic TRAIL receptors, TRAIL-R1 and TRAIL-R2, as well as Bcl-xL and TRAF2 in TRAIL-induced expression of the pro-inflammatory cytokine IL-8 and the invasion-promoting protein urokinase (uPA) in pancreatic ductal adenocarcinoma (PDAC) cells.
  
  
  METHODS
  Colo357wt, Colo357/TRAF2, Colo357/Bcl-xL, Panc89 and PancTuI cells were stimulated with TRAIL and uPA and IL-8 expression was detected using real-time PCR. Antagonistic, receptor-specific antibodies were used to investigate the effects of TRAIL-R1 or TRAIL-R2 inhibition.
  
  
  RESULTS
  Dose-dependent increases in uPA and IL-8 expression were detected following TRAIL stimulation in PDAC cells. These effects were inhibited when TRAIL-R1 but not TRAIL-R2 was blocked. Overexpression of TRAF2 or Bcl-xL strongly increased TRAIL-mediated upregulation of uPA and IL-8.
  
  
  CONCLUSIONS
  In PDAC cells, TRAIL strongly induced uPA and IL-8 via TRAIL-R1. This response was further enhanced in cells overexpressing TRAF2 and Bcl-xL. Therefore, inhibition of the non-apoptotic "side-effects" of TRAIL treatments by inactivation of TRAF2 and Bcl-xL might represent additional relevant strategies for the treatment of pancreatic cancer.
authors: Department of Oncology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. zdh19838@hotmail.com
authors: Dong-Hui
authors: DH
authors: Zhou
authors: Li-Na
authors: LN
authors: Yang
authors: Christian
authors: C
authors: Roder
authors: Holger
authors: H
authors: Kalthoff
authors: Anna
authors: A
authors: Trauzold
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology / Q000628:therapy; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*; D051020:bcl-X Protein / Q000235:genetics*
chemical_list: C494811:BCL2L1 protein, human; C508606:CXCL8 protein, human; D016209:Interleukin-8; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D047992:TNF Receptor-Associated Factor 2; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; D051020:bcl-X Protein; D014568:Urokinase-Type Plasminogen Activator