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-γ

Kebin Liu, Scott I. Abrams

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39 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6329-6337
Number of pages9
JournalJournal of Immunology
Volume170
Issue number12
StatePublished - Jun 15 2003
Externally publishedYes

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Caspase 1
Colon
Apoptosis
Carcinoma
Genes
Neoplasms
Genome
Transcriptome
Interferons
interferon regulatory factor-8
Gene Expression
Cell Line
Population

ASJC Scopus subject areas

  • Immunology

Cite this

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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-γ",
abstract = "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.",
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