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Interferon-gamma inhibits DNA synthesis and insulin-like growth factor-II expression in human neuroblastoma cells
D M Martin1, R O Carlson, E L Feldman
1Department of Neurology, University of Michigan, Ann Arbor.
Abstract:
Interferon-gamma (IFN-gamma) is known to be an antiproliferative, differentiating agent in many cell types, including neuroblastoma. In this study, we determined the effects of IFN-gamma on cellular growth and expression of insulin-like growth factor II (IGF-II) and IGF receptors in the human neuroblastoma cell line SH-SY5Y. Incubation of SH-SY5Y cells in IFN-gamma (20-100 U/ml) induced the formation of long neuritic processes. IFN-gamma treatment also induced decreases in [3H]TdR incorporation, as well as serum-dependent changes in cell number. Treatment with IFN-gamma reduced cell number 33% in the presence of serum but had no effect on cell number in the absence of serum. IGF-II mRNA content was 60% inhibited by IFN-gamma, and was not serum dependent. The concentration of immunoreactive IGF-II in SH-SY5Y conditioned medium was also reduced in the presence of IFN-gamma, to less than half of control levels. In contrast, type I IGF receptor mRNA content was increased more than three-fold after treatment with IFN-gamma and serum. Co-incubation in IFN-gamma (20-100 U/ml) and IGF-II (3-10 nM) prevented the inhibitory effects of IFN-gamma on [3H]TdR incorporation in serum-free media. Our results suggest that IFN-gamma may inhibit DNA synthesis and cell growth by interfering with an IGF-II/type I IGF receptor autocrine growth or survival mechanism.
Insights
Interferon-gamma (IFN-gamma) promotes neuroblastoma cell differentiation and inhibits growth. It reduces insulin-like growth factor II (IGF-II) and upregulates IGF receptors, suggesting a mechanism involving interference with IGF-II signaling.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Interferon-gamma (IFN-gamma) is recognized for its antiproliferative and differentiating effects across various cell types.
- Neuroblastoma, a pediatric cancer, is a significant area of research for novel therapeutic strategies.
- Insulin-like growth factor II (IGF-II) and its receptors play crucial roles in cellular growth and development.
Purpose of the Study:
- To investigate the impact of IFN-gamma on the proliferation and differentiation of the human neuroblastoma cell line SH-SY5Y.
- To determine the effects of IFN-gamma on the expression of IGF-II and its receptors in SH-SY5Y cells.
- To elucidate the potential mechanism by which IFN-gamma influences neuroblastoma cell behavior.
Main Methods:
- SH-SY5Y neuroblastoma cells were cultured and treated with varying concentrations of IFN-gamma.
- Cellular growth was assessed by measuring [3H]TdR incorporation and cell number.
- Gene expression of IGF-II and type I IGF receptor was analyzed using mRNA quantification.
- Quantification of secreted IGF-II in conditioned media was performed.
Main Results:
- IFN-gamma induced neuritic process formation, indicating differentiation in SH-SY5Y cells.
- IFN-gamma treatment decreased [3H]TdR incorporation and cell number in a serum-dependent manner.
- IFN-gamma significantly inhibited IGF-II mRNA expression and secretion, independent of serum.
- Type I IGF receptor mRNA expression was markedly increased following IFN-gamma and serum treatment.
- Co-administration of IGF-II with IFN-gamma partially reversed the inhibitory effects on DNA synthesis.
Conclusions:
- IFN-gamma exhibits antiproliferative and differentiating effects on SH-SY5Y neuroblastoma cells.
- IFN-gamma appears to inhibit cell growth and DNA synthesis by modulating the IGF-II/type I IGF receptor signaling pathway.
- These findings suggest a potential therapeutic role for IFN-gamma in neuroblastoma treatment by disrupting autocrine growth mechanisms.