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

Cancer Res. 2003 Sep 1;63(17):5299-307.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Carrier Proteins / biosynthesis
  • Caspase Inhibitors
  • Caspases / metabolism
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / 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
  • Isoenzymes / metabolism
  • Membrane Glycoproteins / biosynthesis*
  • Membrane Glycoproteins / genetics
  • Promoter Regions, Genetic / drug effects
  • Recombinant Proteins
  • STAT1 Transcription Factor
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • TNF-Related Apoptosis-Inducing Ligand
  • Trans-Activators / physiology*
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / biosynthesis*
  • Tumor Necrosis Factor-alpha / genetics

Substances

  • 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