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Gut. Aug 2001; 49(2): 251–262.
PMCID: PMC1728385

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


BACKGROUND AND AIMS—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 γ (IFN-γ) on growth and survival in human pancreatic cancer cells.
METHODS—IFN-γ 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.
RESULTS—All four pancreatic cancer cell lines examined expressed functional IFN-γ receptors and downstream effectors, including the putative tumour suppressor interferon regulatory factor 1 (IRF-1). IFN-γ 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-γ mediated apoptosis.
CONCLUSIONS—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.

Keywords: interferon γ; apoptosis; caspase-1;interferon regulatory factor; pancreatic cancer

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Figures and Tables

Figure 1
Pancreatic cancer cells express interferon γ receptor (IFN-γ-R) mRNA transcripts. Total mRNA was extracted, reverse transcribed into cDNA, and amplified using polymerase chain reaction with specific primers directed against the ...
Figure 2
Interferon γ (IFN-γ) activates the Jak-Stat signal transduction pathway in human pancreatic cancer cells. Cells were stimulated with 500 IU/ml IFN-γ for the indicated time periods and Jak-1 (A), Jak-2 (B), and ...
Figure 3
Interferon γ (IFN-γ) stimulation results in transactivation of a GAS driven reporter construct. AsPc-1 cells were transiently transfected with pGL2-GAS and relative luciferase activity was measured after a 24 hour period ...
Figure 4
Interferon γ (IFN-γ) inhibits anchorage dependent and independent growth of human pancreatic cancer cells. Subconfluent cells were treated with 500 IU/ml IFN-γ or vehicle for the indicated time periods (A), or ...
Figure 5
Interferon γ (IFN-γ) treated pancreatic tumour cells contain a subdiploid DNA complement. (A) Time course of representative FACS analyses illustrating the cell cycle distribution of pancreatic cancer cells under control conditions ...
Figure 6
Interferon γ (IFN-γ) induced DNA fragmentation and poly(ADP ribose) polymerase (PARP) cleavage in human pancreatic cancer cell lines. (A) Cells were incubated for four days with 500 IU/ml IFN-γ (lanes 3, 5, 7, and ...
Figure 7
Interferon γ (IFN-γ) treatment regulates retinoblastoma protein (pRb) phosphorylation and abundance in human pancreatic cancer cells. Immunoblot analysis demonstrating the time course of changes in pRb expression and phosphorylation ...
Figure 8
Interferon γ (IFN-γ) mediated apoptosis is prevented by the caspase inhibitor z-vad-fmk. Cells were stimulated for three days with either IFN-γ (500 IU/ml), a combination of IFN-γ and z-vad-fmk at various ...
Figure 9
Interferon γ (IFN-γ) causes upregulation of procaspase-1 and interferon regulatory factor 1 (IRF-1) in pancreatic cancer cell lines. (A) Cells were incubated with vehicle or IFN-γ (500 IU/ml) for the indicated ...

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