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TRAIL-induced expression of uPA and IL-8 strongly enhanced by overexpression of TRAF2 and Bcl-xL in pancreatic ductal adenocarcinoma cells |
Dong-Hui Zhou, Li-Na Yang, Christian Röder, Holger Kalthoff and Anna Trauzold |
Hangzhou, China
Author Affiliations: Department of Oncology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Zhou DH and Yang LN); Division of Molecular Oncology, Institute of Experimental Cancer Research, CCC-North, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany (Röder C, Kalthoff H and Trauzold A)
Corresponding Author: Dong-Hui Zhou, MD, Department of Oncology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China (Tel: 86-571-87236878; Fax: 86-571-86027898; Email: zdh19838@hotmail.com) |
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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.
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