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