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Increased Expression of the E3-Ubiquitin Ligase Receptor Subunit ßTRCP1 Relates to Constitutive Nuclear Factor-B Activation and Chemoresistance in Pancreatic Carcinoma Cells

¹ Laboratory of Molecular Gastroenterology and Hepatology, First Department of Medicine, ² Department of Pathology, and ³ Molecular Oncology Research Group, Department of General Surgery, Kiel University, UKSH Campus-Kiel, Kiel, Germany

Requests for reprints: Heiner Schäfer, Laboratory of Molecular Gastroenterology and Hepatology, First Department of Medicine, University of Kiel, UKSH-Campus Kiel, Schittenhelmstraße 12, 24105 Kiel, Germany. Phone: 49-431-597-1266/1394; Fax: 49-431-597-1427; E-mail: hschaef{at}1med.uni-kiel.de.

The permanent activation of the transcription factor nuclear factor-B (NF-B) in pancreatic cancer cells is associated with a profound resistance towards chemotherapy. In the present study, we show that chemoresistant pancreatic cancer cell lines exhibiting constitutive NF-B activity (i.e., PancTu-1, BxPc3, and Capan-1) express significantly elevated levels of the E3-ubiquitin ligase receptor subunit ßTRCP1, compared with pancreatic carcinoma cell lines lacking constitutive NF-B activity and chemoresistance (i.e., PT45-P1 and T3M4). If transfected with ßTRCP1, PT45-P1 cells exhibit an elevated NF-B activity and become less sensitive towards anticancer drug treatment (i.e., etoposide). Conversely, blockade of ßTRCP1 expression in PancTu-1 cells by transfection with a vector-expressed small interfering RNA reduces NF-B activation and chemoresistance. In PancTu-1 cells, ßTRCP1 expression is inhibited, at least in part, by the interleukin-1 (IL-1) receptor(I) antagonist, whereas stimulation of PT45-P1 cells with IL-1ß resulted in an increased expression of ßTRCP1, and transfection of this cell line with ßTRCP1 induced IL-1ß secretion in a NF-B–dependent fashion. Thus, via its close and mutual link to IL-1ß secretion, ßTRCP1 expression might substantially contribute to the persistent, IL-1ß–dependent activation of NF-B in pancreatic carcinoma cells. In support of this, ßTRCP1 expression is detectable at considerable levels in a great number of pancreatic ductal adenocarcinoma specimens, along with an intense staining for activated NF-B. Altogether, our findings of the elevated ßTRCP1 expression in pancreatic carcinoma cells pinpoint to another important mediator of constitutive NF-B activation and thereby of chemoresistance.

Key Words: chemoresistance • pancreatic carcinoma • ubiquitin ligase • siRNA

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