Increased expression of the E3-ubiquitin ligase receptor subunit βTRCP1 relates to constitutive nuclear factor-κB activation and chemoresistance in pancreatic carcinoma cells

Susanne Müerköster, Alexander Arlt, Bence Sipos, Maike Witt, Maike Großmann, Günter Klöppel, Holger Kalthoff, Ulrich R. Fölsch, Heiner Schäfer

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

Abstract

The permanent activation of the transcription factor nuclear factor-κB (NF-κB) 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-κB activity (i.e., PancTu-1, BxPc3, and Capan-1) express significantly elevated levels of the E3-ubiquitin ligase receptor subunit βTRCP1, compared with pancreatic carcinoma cell lines lacking constitutive NF-κB activity and chemoresistance (i.e., PT45-P1 and T3M4). If transfected with βTRCP1, PT45-P1 cells exhibit an elevated NF-κB activity and become less sensitive towards anticancer drug treatment (i.e., etoposide). Conversely, blockade of βTRCP1 expression in PancTu-1 cells by transfection with a vector-expressed small interfering RNA reduces NF-κB activation and chemoresistance. In PancTu-1 cells, βTRCP1 expression is inhibited, at least in part, by the interleukin-1 (IL-1) receptor(I) antagonist, whereas stimulation of PT45-P1 cells with IL-1β resulted in an increased expression of βTRCP1, and transfection of this cell line with βTRCP1 induced IL-1β secretion in a NF-κB-dependent fashion. Thus, via its close and mutual link to IL-1β secretion, βTRCP1 expression might substantially contribute to the persistent, IL-1β-dependent activation of NF-κB in pancreatic carcinoma cells. In support of this, βTRCP1 expression is detectable at considerable levels in a great number of pancreatic ductal adenocarcinoma specimens, along with an intense staining for activated NF-κB. Altogether, our findings of the elevated βTRCP1 expression in pancreatic carcinoma cells pinpoint to another important mediator of constitutive NF-κB activation and thereby of chemoresistance.

Original languageEnglish
Pages (from-to)1316-1324
Number of pages9
JournalCancer Research
Volume65
Issue number4
DOIs
StatePublished - 15 Feb 2005
Externally publishedYes

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