SAHA down-regulates the expression of indoleamine 2,3-dioxygenase via inhibition of the JAK/STAT1 signaling pathway in gallbladder carcinoma cells

Oncol Rep. 2013 Jan;29(1):269-75. doi: 10.3892/or.2012.2073. Epub 2012 Oct 8.

Abstract

The aim of the present study was to investigate the role of the JAK/STAT1 signaling pathway in suberoylanilide hydroxamic acid (SAHA)-mediated down-regulation of indoleamine 2,3-dioxygenase (IDO) in gallbladder carcinoma cells. We treated SGC-996 gallbladder carcinoma cells with IFN-γ and SAHA. Western blotting was used to detect the expression of IDO, signal transducer and activator of transcription 1 (STAT1) phosphorylation and interferon regulatory factor genes-1 (IRF-1). Confocal microscopy analysis was used to detect STAT1 translocation. Transient transfection and reporter gene assay was used for detecting the activation of γ-activated sites (GAS) and interferon-stimulated response elements (ISRE). The results revealed that IDO was expressed in SGC-996 cells in a dose- and time-dependent manner when stimulated with IFN-γ and SAHA down-regulated the expression of IDO induced by IFN-γ in a dose-dependent manner. SAHA blocked the expression of IRF-1 induced by IFN-γ and SAHA inhibited IFN-γ-induced STAT1 phosphorylation and nuclear translocation. In addition, SAHA down-regulated IFN-γ-induced activation of GAS and ISRE. In conclusion, SAHA down-regulated IDO expression via inhibition of the activation of members of the JAK/STAT1 signaling pathway. Therefore, regulation of the JAK/STAT1 signaling pathway may provide a new gallbladder carcinoma immunotherapeutic strategy to break tumor immune tolerance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antiviral Agents / pharmacology
  • Blotting, Western
  • Gallbladder Neoplasms / mortality
  • Gallbladder Neoplasms / pathology*
  • Gallbladder Neoplasms / therapy
  • Gene Expression Regulation, Enzymologic / drug effects
  • Humans
  • Hydroxamic Acids / pharmacology*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Interferon-gamma / pharmacology
  • Janus Kinases / antagonists & inhibitors*
  • Janus Kinases / metabolism
  • Phosphorylation / drug effects
  • Protein Transport / drug effects
  • STAT1 Transcription Factor / antagonists & inhibitors*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / drug effects*
  • Tumor Cells, Cultured
  • Vorinostat

Substances

  • Antineoplastic Agents
  • Antiviral Agents
  • Hydroxamic Acids
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • STAT1 Transcription Factor
  • Vorinostat
  • Interferon-gamma
  • Janus Kinases