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1: Cancer Res. 2005 Feb 15;65(4):1316-24.
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Increased expression of the E3-ubiquitin ligase receptor subunit betaTRCP1 relates to constitutive nuclear factor-kappaB activation and chemoresistance in pancreatic carcinoma cells.

Müerköster S, Arlt A, Sipos B, Witt M, Grossmann M, Klöppel G, Kalthoff H, Fölsch UR, Schäfer H.

Laboratory of Molecular Gastroenterology and Hepatology, First Department of Medicine, Kiel University, UKSH Campus-Kiel, Kiel, Germany.

The permanent activation of the transcription factor nuclear factor-kappaB (NF-kappaB) 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-kappaB activity (i.e., PancTu-1, BxPc3, and Capan-1) express significantly elevated levels of the E3-ubiquitin ligase receptor subunit betaTRCP1, compared with pancreatic carcinoma cell lines lacking constitutive NF-kappaB activity and chemoresistance (i.e., PT45-P1 and T3M4). If transfected with betaTRCP1, PT45-P1 cells exhibit an elevated NF-kappaB activity and become less sensitive towards anticancer drug treatment (i.e., etoposide). Conversely, blockade of betaTRCP1 expression in PancTu-1 cells by transfection with a vector-expressed small interfering RNA reduces NF-kappaB activation and chemoresistance. In PancTu-1 cells, betaTRCP1 expression is inhibited, at least in part, by the interleukin-1 (IL-1) receptor(I) antagonist, whereas stimulation of PT45-P1 cells with IL-1beta resulted in an increased expression of betaTRCP1, and transfection of this cell line with betaTRCP1 induced IL-1beta secretion in a NF-kappaB-dependent fashion. Thus, via its close and mutual link to IL-1beta secretion, betaTRCP1 expression might substantially contribute to the persistent, IL-1beta-dependent activation of NF-kappaB in pancreatic carcinoma cells. In support of this, betaTRCP1 expression is detectable at considerable levels in a great number of pancreatic ductal adenocarcinoma specimens, along with an intense staining for activated NF-kappaB. Altogether, our findings of the elevated betaTRCP1 expression in pancreatic carcinoma cells pinpoint to another important mediator of constitutive NF-kappaB activation and thereby of chemoresistance.

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PMID: 15735017 [PubMed - indexed for MEDLINE]