Evaluation of IFN-gamma effects on apoptosis and gene expression in neuroblastoma--preclinical studies

Biochim Biophys Acta. 2006 Oct;1763(10):1000-10. doi: 10.1016/j.bbamcr.2006.06.014. Epub 2006 Aug 9.

Abstract

Loss of caspase-8 expression and resistance to cytotoxic agents occurs frequently in late stage neuroblastoma (NB). Interferon-gamma (IFN-gamma) induces caspase-8 in NB cells, sensitizing them to death receptor mediated apoptosis. This study characterizes the kinetics of this phenomenon and examines the effects of IFN-gamma on global gene expression to determine whether IFN-gamma responses are achievable at physiologically relevant doses and to define the biological effects of this cytokine. Here we examine the IFN-gamma responses of 16 NB cell lines. A single <5-min exposure to IFN-gamma (0.5 ng/ml) induced caspase-8 expression in all non-expressing cell lines and in 3/6 cell lines which already expressed high caspase-8. This increase in caspase-8 proteins was observed within 16 h and persisted for up to 9 days. Furthermore, IFN-gamma pretreatment of NB cells increased doxorubicin-induced apoptosis nearly 3-fold. Microarray analysis was used to identify additional genes involved in proliferation, signaling and apoptosis whose expression was modulated via IFN-gamma. Altered expression of these genes should further enhance the responsiveness of NB cells to chemotherapeutics. Thus, the use of IFN-gamma to sensitize NB cells to cytotoxic agents represents an attractive therapeutic strategy and warrants further investigation.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • Caspase 8 / metabolism
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Doxorubicin / pharmacology
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Interferon-gamma / pharmacology*
  • Methylation
  • Neuroblastoma / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Time Factors

Substances

  • RNA, Messenger
  • Doxorubicin
  • Interferon-gamma
  • Caspase 8