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Nitric oxide mediates apoptosis induction selectively in transformed fibroblasts compared to nontransformed
Stefanie Heigold1, Christine Sers, Wibke Bechtel
1Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, D-79104 Freiburg, Germany.
Abstract:
Nitric oxide (NO) mediates apoptosis induction in fibroblasts with constitutive src or induced ras oncogene expression, whereas nontransformed parental cells and revertants are not affected. This direct link between the transformed phenotype and sensitivity to NO-mediated apoptosis induction seems to be based on the recently described extracellular superoxide anion generation by transformed cells, as NO-mediated apoptosis induction in transformed cells is inhibited by extracellular superoxide dismutase (SOD), by SOD mimetics and by apocynin, an inhibitor of NADPH oxidase. Furthermore, nonresponsive nontransformed cells can be rendered sensitive for NO-mediated apoptosis induction when they are supplemented with xanthine oxidase/xanthine as an extracellular source for superoxide anions. As superoxide anions and NO readily interact in a diffusion-controlled reaction to generate peroxynitrite, peroxynitrite seems to be the responsible apoptosis inducer in NO-mediated apoptosis induction. In line with this conclusion, NO-mediated apoptosis induction in superoxide anion-generating transformed cells is inhibited by the peroxynitrite scavengers ebselen and FeTPPS. Moreover, direct application of peroxynitrite induces apoptosis both in transformed and nontransformed cells, indicating that peroxynitrite is no selective apoptosis inducer per se, but that selective apoptosis induction in transformed cells by NO is achieved through selective peroxynitrite generation. The interaction of NO with target cell derived superoxide anions represents a novel concept for selective apoptosis induction in transformed cells. This mechanism may be the basis for selective apoptosis induction by natural antitumor systems (like macrophages, natural killer cells, granulocytes) that utilize NO for antitumor action. Apoptosis induction mediated by NO involves mitochondrial depolarization and is blocked by Bcl-2 overexpression.
Insights
Nitric oxide (NO) induces apoptosis in transformed cells via extracellular superoxide anion generation, leading to peroxynitrite formation. This selective mechanism targets cancer cells and may explain natural anti-tumor responses.
Area of Science:
- Cell Biology
- Biochemistry
- Cancer Research
Background:
- Nitric oxide (NO) is known to mediate apoptosis.
- Transformed cells exhibit unique responses to NO compared to normal cells.
Purpose of the Study:
- To elucidate the mechanism by which NO induces apoptosis selectively in transformed cells.
- To identify the key reactive species involved in NO-mediated apoptosis.
Main Methods:
- Investigated NO-induced apoptosis in fibroblasts with oncogene expression.
- Utilized superoxide dismutase (SOD), SOD mimetics, apocynin, and peroxynitrite scavengers.
- Assessed apoptosis induction with and without extracellular superoxide anion sources.
Main Results:
- Transformed cells, but not normal cells, showed NO-mediated apoptosis.
- Extracellular superoxide anion generation by transformed cells was crucial for NO-induced apoptosis.
- Peroxynitrite formation, resulting from NO and superoxide interaction, was identified as the apoptosis inducer.
- Direct peroxynitrite application induced apoptosis in all cell types, but NO selectively induced it in transformed cells via peroxynitrite generation.
Conclusions:
- NO selectively induces apoptosis in transformed cells through the generation of peroxynitrite, driven by cell-derived superoxide anions.
- This mechanism highlights a novel pathway for selective cancer cell apoptosis.
- The findings suggest potential applications for NO-based cancer therapies and explain the role of NO in natural anti-tumor immunity.