Autocrine production of interleukin 1beta confers constitutive nuclear factor kappaB activity and chemoresistance in pancreatic carcinoma cell lines.
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.
Arlt
Alexander
A
Laboratory of Molecular Gastroenterology, Department of Medicine, University of Kiel, Schittenhelmstrasse 12, D-24105 Kiel, Germany.
Vorndamm
Jens
J
Müerköster
Susanne
S
Yu
Honggang
H
Schmidt
Wolfgang E
WE
Fölsch
Ulrich R
UR
Schäfer
Heiner
H
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
D000972:Antineoplastic Agents, Phytogenic; D007375:Interleukin-1; D016328:NF-kappa B; D005047:Etoposide