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PMID: 11454803 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Interferon gamma inhibits growth of human pancreatic carcinoma cells via caspase-1 dependent induction of apoptosis.

Gut ·Vol. 49 ·No. 2 ·2001-08-00 ·Pages 251-62

Detjen KM, Farwig K, Welzel M, Wiedenmann B, Rosewicz S

Abstract

The poor prognosis of pancreatic cancer is partly due to resistance to a broad spectrum of apoptotic stimuli. To identify intact proapoptotic pathways of potential clinical relevance, we characterised the effects of interferon gamma (IFN-gamma) on growth and survival in human pancreatic cancer cells. IFN-gamma receptor expression and signal transduction were examined by reverse transcriptase-polymerase chain reaction (RT-PCR), immunoprecipitation, western blot analysis, and transactivation assays. Effects on cell growth and survival were evaluated in terms of cell numbers, colony formation, cell cycle analysis, DNA fragmentation, and poly(ADP ribose) polymerase (PARP) cleavage. All four pancreatic cancer cell lines examined expressed functional IFN-gamma receptors and downstream effectors, including the putative tumour suppressor interferon regulatory factor 1 (IRF-1). IFN-gamma treatment profoundly inhibited anchorage dependent and independent growth of pancreatic cancer cells. Cell cycle analyses revealed subdiploid cells suggesting apoptosis, which was confirmed by demonstration of DNA fragmentation and PARP cleavage. Time and dose dependency of apoptosis induction and growth inhibition correlated closely, identifying apoptosis as the main, if not exclusive, mechanism responsible for growth inhibition. Apoptosis was preceded by upregulation of procaspase-1 and accompanied by proteolytic activation. Furthermore, the caspase inhibitor z-vad-fmk completely prevented IFN-gamma mediated apoptosis. These results identify an intact proapoptotic pathway in pancreatic cancer cells and suggest that IRF-1 and/or procaspase-1 may represent potential therapeutic targets to be further explored.

MeSH Terms
Analysis of Variance Apoptosis/physiology Blotting, Western Caspase 1/physiology Cell Count Cell Division/drug effects Cell Survival/drug effects DNA Fragmentation/drug effects Dose-Response Relationship, Drug Enzyme-Linked Immunosorbent Assay Humans Interferon-gamma/therapeutic use Pancreatic Neoplasms/drug therapy,pathology Precipitin Tests Receptors, Interferon/physiology Reverse Transcriptase Polymerase Chain Reaction Signal Transduction/physiology Transcriptional Activation/physiology Tumor Cells, Cultured/drug effects Up-Regulation
Chemicals
Receptors, Interferon Interferon-gamma Caspase 1
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Detjen K M
Medizinische Klinik mit Schwerpunkt Hepatologie und Gastroenterologie, Universitätsklinikum Charité, Campus Virchow Klinikum, Humboldt Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Farwig K
Welzel M
Wiedenmann B
Rosewicz S
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Article Info
Journal
Gut
Abbr.
Gut
ISSN
0017-5749
DOI
10.1136/gut.49.2.251
Published
2001-08-00
Pages
251-62
Language
English
Region
England
NLM ID
2985108R
PMCID
PMC1728385
Subset
IM
External Links
PubMed source DOI: 10.1136/gut.49.2.251 PMC Full Text View journal details
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