title: Autocrine production of interleukin 1beta confers constitutive nuclear factor kappaB activity and chemoresistance in pancreatic carcinoma cell lines.
abstract: We have recently shown that several pancreatic carcinoma cell lines are resistant to topoisomerase IIalpha inhibitors due to elevated basal nuclear factor kappaB (NF-kappaB) activity, and blockade of this activity by various means strongly increased chemosensitivity. In search of possible mechanisms leading to exaggerated NF-kappaB activity, we identified interleukin (IL)-1beta as a key mediator of this activation in two of the chemoresistant cell lines (A818-4 and PancTu-1). These cells express and secrete high levels of IL-1beta, as demonstrated by reverse transcription-PCR, immunocytochemistry, and ELISA. Culture supernatants from both cell lines induced NF-kappaB activity in chemosensitive PT45-P1 pancreatic carcinoma cells and significantly attenuated etoposide-induced apoptosis in a NF-kappaB-dependent fashion, similar to that seen in PT45-P1 cells treated with recombinant IL-1beta. Treatment of these cells with IL-1beta also changed the DNA damage characteristics toward those observed in A818-4 and PancTu-1 cells. NF-kappaB activation and the gain of chemoresistance in PT45-P1 cells on treatment with supernatants from both chemoresistant cell lines was abolished in the presence of a blocking anti-IL-1 receptor (I) antibody. Furthermore, this antibody decreased the resistance of A818-4 and PancTu-1 cells to etoposide treatment along with reduced NF-kappaB activity. Blockade of NF-kappaB activation by MG132, sulfasalazine, or an IkappaBalpha superrepressor disrupted the IL-1beta-mediated amplification loop and the accompanying chemoresistance. Our data provide insights into an autocrine mechanism involving IL-1beta by which pancreatic carcinoma cells develop chemoresistance that could serve as a molecular target in anticancer therapy.
authors.affiliation: Laboratory of Molecular Gastroenterology, Department of Medicine, University of Kiel, Schittenhelmstrasse 12, D-24105 Kiel, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Arlt
authors.forename: Jens
authors.initials: J
authors.lastname: Vorndamm
authors.forename: Susanne
authors.initials: S
authors.lastname: Müerköster
authors.forename: Honggang
authors.initials: H
authors.lastname: Yu
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Schmidt
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*; D017209:Apoptosis / Q000187:drug effects; D004249:DNA Damage; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D007375:Interleukin-1; D016328:NF-kappa B; D005047:Etoposide