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Evaluation of IFN-gamma effects on apoptosis and gene expression in neuroblastoma--preclinical studies
Tanya M Tekautz1, Kejin Zhu, Jose Grenet
1Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
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.
Insights
Interferon-gamma (IFN-gamma) restores caspase-8 expression in neuroblastoma cells, enhancing their sensitivity to chemotherapy. This cytokine offers a promising therapeutic strategy for advanced neuroblastoma.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Late-stage neuroblastoma (NB) often exhibits loss of caspase-8 and resistance to cytotoxic agents.
- Interferon-gamma (IFN-gamma) can induce caspase-8 expression in NB cells, sensitizing them to apoptosis.
- Understanding IFN-gamma's kinetics and gene expression effects is crucial for therapeutic application.
Purpose of the Study:
- To characterize the kinetics of IFN-gamma-induced caspase-8 expression in NB cells.
- To determine if IFN-gamma responses are achievable at physiologically relevant doses.
- To identify genes modulated by IFN-gamma that impact NB cell biology and chemosensitivity.
Main Methods:
- Exposure of 16 NB cell lines to a single, short dose of IFN-gamma (0.5 ng/ml).
- Assessment of caspase-8 protein levels over time (within 16h to 9 days).
- Microarray analysis to evaluate global gene expression changes induced by IFN-gamma.
Main Results:
- A brief IFN-gamma exposure induced caspase-8 expression in all tested NB cell lines lacking it.
- Increased caspase-8 protein levels were sustained for up to 9 days.
- IFN-gamma pretreatment significantly enhanced doxorubicin-induced apoptosis (nearly 3-fold) and modulated genes involved in proliferation, signaling, and apoptosis.
Conclusions:
- IFN-gamma effectively re-establishes caspase-8 expression and sensitizes neuroblastoma cells to apoptosis.
- Physiologically relevant doses of IFN-gamma can induce sustained therapeutic effects.
- IFN-gamma represents a promising strategy to enhance neuroblastoma cell responsiveness to cytotoxic agents.
