title: Coordinate regulation of IFN consensus sequence-binding protein and caspase-1 in the sensitization of human colon carcinoma cells to Fas-mediated apoptosis by IFN-gamma.
abstract: Interferon-gamma is thought to be essential for the regulation of antitumor reactions. However, the degree of responsiveness of malignant cells to IFN-gamma may have a profound influence on the overall efficacy of an antitumor response. In this study, we examined the molecular basis by which IFN-gamma differentially sensitized human primary and metastatic colon carcinoma cells to Fas-mediated apoptosis. To that end, we analyzed IFN-gamma-induced gene expression at the genome scale, followed by an analysis of the expression and function of specific genes associated with IFN-gamma- and Fas-mediated signaling. We found that although both cell populations exhibited a similar gene expression profile at the genome scale in response to IFN-gamma, the expression intensities of the IFN-gamma-regulated genes were much greater in the primary tumor. Noteworthily, two genes, one involved in IFN-gamma-mediated signaling, IFN consensus sequence-binding protein (ICSBP), and one involved in Fas-mediated signaling, caspase-1, were clearly shown to be differentially induced between the two cell lines. In the primary tumor cells, the expression of ICSBP and caspase-1 was strongly induced in response to IFN-gamma, whereas they were weakly to nondetectable in the metastatic tumor cells. Functional studies demonstrated that both caspase-1 and ICSBP were involved in Fas-mediated apoptosis following IFN-gamma sensitization, but proceeded via two distinct pathways. This study also reports for the first time the expression of ICSBP in a nonhemopoietic tumor exhibiting proapoptotic properties. Overall, in a human colon carcinoma cell model, we identified important functional contributions of two IFN-gamma-regulated genes, ICSBP and caspase-1, in the mechanism of Fas-mediated death.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
authors.forename: Scott I
authors.initials: SI
authors.lastname: Abrams
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D020170:Caspase 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D016384:Consensus Sequence; D004790:Enzyme Induction / Q000235:genetics / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D015894:Genome, Human; D006801:Humans; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma / Q000502:physiology*; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000096:biosynthesis / Q000502:physiology*; D000099185:Interferon Regulatory Factor-8
chemical_list: D020170:Caspase 1; D050835:Interferon Regulatory Factors; D007371:Interferon-gamma; D012097:Repressor Proteins; D019014:fas Receptor; D000099185:Interferon Regulatory Factor-8