Synthesis and biological effects of NO in malignant glioma cells: modulation by cytokines including CD95L and TGF-β dexamethasone, and p53 gene transfer

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Abstract

Nitric oxide (NO) is thought to play an important role in neurotransmission, inflammation, and regulation of cell death in the mammalian brain. Here, we examined the synthesis and biological effects of NO in human malignant glioma cells. Exposure to cytokines such as interferon (IFN)-γ, tumor necrosis factor (TNF)-α or interleukin (IL)-1β and lipopolysaccharide (LPS) induced NO synthesis in rat C6 and A172 human glioma cells, but not in LN-229, T98G or LN-18 human malignant glioma cells. Induced release of NO involved enhanced expression of inducible NO synthase (iNOS). Failure to detect NO release in the latter cell lines was not overcome by neutralization of endogenous TGF-β or by coexposure to cytokines, LPS, and antioxidants. Apoptosis induced by CD95 ligand (CD95L) did not involve NO formation. Neither NOS inhibitors nor NO donators modulated CD95L-induced apoptosis. Dexamethasone (DEX)-mediated protection of glioma cells from CD95L-induced apoptosis was also independent of DEX effects on NO metabolism. DEX inhibited not only cytokine/ LPS-evoked NO release but also attenuated the toxicity of NO in three of five cell lines. Forced expression of temperature-sensitive p53 val135 in C6 cells in either mutant or wild-type conformation inhibited cytokine/LPS-induced NO synthesis. Further, accumulation of p53 in both mutant or wild-type conformation protected glioma cells from the toxicity of exogenous NO, consistent with a gain of p53 function associated with p53 accumulation. We conclude that resistance to NO-dependent immune defense mechanisms may contribute to the malignant progression of human cancers with p53 alterations, notably those associated with the accumulation of mutant p53 protein.

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Correspondence to Michael Weller.

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Rieger, J., Ständer, M., Löschmann, P. et al. Synthesis and biological effects of NO in malignant glioma cells: modulation by cytokines including CD95L and TGF-β dexamethasone, and p53 gene transfer. Oncogene 17, 2323–2332 (1998) doi:10.1038/sj.onc.1202154

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Keywords

  • Nitric oxide
  • glioma
  • CD 95 ligand
  • p53