[Autocrine IL-1beta secretion leads to NF-kappabeta-mediated chemoresistance in pancreatic carcinoma cells in vivo].
OBJECTIVE
The pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly malignant phenotype and a profound chemoresistance. Thus, options for an effective treatment of this disease are still quite poor. In this study, it was investigated whether the autocrine secretion of interleukin-(IL-)1beta is related to a chemoresistant phenotype of PDAC cells in vivo.


METHODS
Human PancTu1 PDAC cells were inoculated subcutaneously into female SCID mice. After 10 days of outgrowth, animals were randomized and left untreated or treated with an IL-1beta-RI antibody, etoposide, or a combination of both. After treatment for 14 days, tumor sizes were determined and each tumor was analyzed immunohistochemically for apoptosis (TUNEL), activated NF-kappaB (p65), and vascularization (CD31 staining).


RESULTS
The combination of IL-1beta-RI antibody and etoposide led to a significantly reduced outgrowth of PancTu1 tumors in comparison to the monotherapies or no treatment. Accordingly, the number of apoptotic cells was significantly elevated in tumors of the combination group. After treatment with the IL-1beta-RI antibody, less activated NF-kappaB was present in tumors compared to the control group. Moreover, tumors of the combination group showed a clearly reduced vascularization.


CONCLUSIONS
The autocrine secretion of IL-1beta contributes to a constitutively increased NF-kappaB activity in PDAC cells along with a chemoresistant phenotype.
Müerköster
Susanne
S
Labor für Molekulare Gastroenterologie und Hepatologie, Klinik für Allgemeine Innere Medizin, UKSH-Campus Kiel, Kiel.
Arlt
Alexander
A
Gehrz
André
A
Vorndamm
Jens
J
Witt
Maike
M
Grohmann
Frauke
F
Fölsch
Ulrich R
UR
Schäfer
Heiner
H
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D019898:Autocrine Communication / Q000502:physiology*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011994:Recombinant Proteins / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000473:pathology; D014410:Tumor Stem Cell Assay
C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D016328:NF-kappa B; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D005047:Etoposide