Stat1-dependent induction of tumor necrosis factor-related apoptosis-inducing ligand and the cell-surface death signaling pathway by interferon beta in human cancer cells.

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.

• Authors: Eugene A Choi, Hanqin Lei, David J Maron, James M Wilson, James Barsoum, Douglas L Fraker, Wafik S El-Deiry, Francis R Spitz
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 17 Pg. 5299-307 (Sep 01 2003) ISSN: 0008-5472 [Print] United States
• PMID: 14500361 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• Carrier Proteins
• Caspase Inhibitors
• DNA-Binding Proteins
• Interferon Type I
• Intracellular Signaling Peptides and Proteins
• Isoenzymes
• Membrane Glycoproteins
• Recombinant Proteins
• STAT1 Transcription Factor
• STAT1 protein, human
• TNF-Related Apoptosis-Inducing Ligand
• TNFSF10 protein, human
• Trans-Activators
• Tumor Necrosis Factor-alpha
• Caspases

Topics

• Adenocarcinoma (drug therapy, metabolism, pathology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, physiology)
• Apoptosis Regulatory Proteins
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Carrier Proteins (biosynthesis)
• Caspase Inhibitors
• Caspases (metabolism)
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• DNA-Binding Proteins (physiology)
• Enzyme Activation (drug effects)
• Gene Expression Regulation, Neoplastic
• Humans
• Interferon Type I (pharmacology)
• Intracellular Signaling Peptides and Proteins
• Isoenzymes (antagonists & inhibitors, metabolism)
• Membrane Glycoproteins (biosynthesis, genetics)
• Promoter Regions, Genetic (drug effects)
• Recombinant Proteins
• STAT1 Transcription Factor
• Signal Transduction (drug effects, physiology)
• TNF-Related Apoptosis-Inducing Ligand
• Trans-Activators (physiology)
• Tumor Cells, Cultured
• Tumor Necrosis Factor-alpha (biosynthesis, genetics)