title: Increased expression of the E3-ubiquitin ligase receptor subunit betaTRCP1 relates to constitutive nuclear factor-kappaB activation and chemoresistance in pancreatic carcinoma cells.
abstract: 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.
authors.affiliation: Laboratory of Molecular Gastroenterology and Hepatology, First Department of Medicine, Kiel University, UKSH Campus-Kiel, Kiel, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Müerköster
authors.forename: Alexander
authors.initials: A
authors.lastname: Arlt
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.forename: Maike
authors.initials: M
authors.lastname: Witt
authors.forename: Maike
authors.initials: M
authors.lastname: Grossmann
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.forename: Ulrich R
authors.initials: UR
authors.lastname: Fölsch
authors.forename: Heiner
authors.initials: H
authors.lastname: Schäfer
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000494:pharmacology; D014162:Transfection; D044844:beta-Transducin Repeat-Containing Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D020672:I-kappa B Proteins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D016328:NF-kappa B; D012795:Sialoglycoproteins; D044844:beta-Transducin Repeat-Containing Proteins; D005047:Etoposide