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Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
Interferon-
is thought to be essential for the regulation of antitumor reactions. However, the degree of responsiveness of malignant cells to IFN- may have a profound influence on the overall efficacy of an antitumor response. In this study, we examined the molecular basis by which IFN- differentially sensitized human primary and metastatic colon carcinoma cells to Fas-mediated apoptosis. To that end, we analyzed IFN--induced gene expression at the genome scale, followed by an analysis of the expression and function of specific genes associated with IFN-- 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-, the expression intensities of the IFN--regulated genes were much greater in the primary tumor. Noteworthily, two genes, one involved in IFN--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-, 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- 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--regulated genes, ICSBP and caspase-1, in the mechanism of Fas-mediated death.
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