Abstract
Type I IFNs are known to inhibit tumor cell growth and stimulate the immune system. However, little is known of the mechanism of type I IFN-induced apoptosis in human cancer cells. In this study, we have IFN-beta treatment of a human colorectal cell line (KM12L4) and a resistant clone of this cell line, L4RIFN. We demonstrate the induction of apoptosis in the parent cell line. This process was associated with the induction of the Jak-Stat signaling pathway, induction of the proapoptotic mediator tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and activation of procaspase-3, -8, -9, and -10. Additionally, we evaluated the role of Stat1 in mediating IFN-beta induction of these proapoptotic signals in a fibrosarcoma cell line (2ftgh) and a Stat1-deficient clone (U3A). Our results demonstrate that IFN-beta induction of apoptosis and the induction of proapoptotic mediator TRAIL is Stat1 dependent. Evaluation of a stable transfectant of the KM12L4 cell line expressing c-FLIP supports the role of TRAIL and the cell-surface death signaling pathways in IFN-beta induction of apoptosis. Studies evaluating the TRAIL promoter indicate induction of TRAIL promoter activity by IFN-beta. These results may represent a novel pathway by which IFN-beta may induce therapeutic effects.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Apoptosis / physiology
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Apoptosis Regulatory Proteins
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Carrier Proteins / biosynthesis
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Caspase Inhibitors
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Caspases / metabolism
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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DNA-Binding Proteins / physiology*
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Enzyme Activation / drug effects
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Gene Expression Regulation, Neoplastic
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Humans
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Interferon Type I / pharmacology*
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Intracellular Signaling Peptides and Proteins*
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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Membrane Glycoproteins / biosynthesis*
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Membrane Glycoproteins / genetics
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Promoter Regions, Genetic / drug effects
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Recombinant Proteins
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STAT1 Transcription Factor
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Signal Transduction / drug effects
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Signal Transduction / physiology
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TNF-Related Apoptosis-Inducing Ligand
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Trans-Activators / physiology*
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Tumor Cells, Cultured
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Tumor Necrosis Factor-alpha / biosynthesis*
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Tumor Necrosis Factor-alpha / genetics
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Carrier Proteins
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Caspase Inhibitors
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DNA-Binding Proteins
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Interferon Type I
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Intracellular Signaling Peptides and Proteins
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Isoenzymes
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Membrane Glycoproteins
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Recombinant Proteins
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STAT1 Transcription Factor
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STAT1 protein, human
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Trans-Activators
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Tumor Necrosis Factor-alpha
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Caspases