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An alternative signaling pathway based on nitryl chloride during intercellular induction of apoptosis
1Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Germany.
Abstract:
Transforming growth factor (TGF)-beta pretreated nontransformed fibroblasts induce apoptosis selectively in transformed fibroblasts. This potential control step during oncogenesis has been termed intercellular induction of apoptosis. Selectivity and efficiency of intercellular induction of apoptosis depend on transformed target cell-derived superoxide anions that drive two intercellular signaling pathways--the HOCl/hydroxyl radical and the nitric oxide (NO)/peroxynitrite pathway. Other natural antitumor systems like macrophages or cells of the granulocyte lineage seem to utilize the same signaling chemistry. Our data demonstrate the existence of an alternative signaling pathway in these systems. This pathway depends on the presence of nitrite and is still effective when the two conventional signaling pathways are blocked by superoxide dismutase (SOD). Nitrite-dependent apoptosis induction is neither blocked by SOD nor by the hydroxyl radical scavenger terephthalate, but it is inhibited by the peroxidase inhibitor aminobenzoyl hydrazide and by the hypochlorous acid (HOCl) scavenger taurine. Therefore, nitrite, that is nontoxic for our cells, seems to interact with HOCl to form the apoptosis inducer nitryl chloride. Nitryl chloride-mediated apoptosis induction might be relevant for apoptosis induction in tumor cells that release SOD and thus escape the two classical signaling pathways.
Insights
Transforming growth factor-beta triggers apoptosis in cancer cells via intercellular signaling. A novel nitrite-dependent pathway, involving nitryl chloride, offers an alternative route for cancer cell apoptosis induction.
Area of Science:
- Cell Biology
- Oncology
- Biochemistry
Background:
- Transforming growth factor-beta (TGF-beta) can induce apoptosis in transformed fibroblasts.
- Intercellular induction of apoptosis is a potential cancer control mechanism.
- Conventional pathways involve superoxide anions, hypochlorous acid (HOCl)/hydroxyl radical, and nitric oxide (NO)/peroxynitrite.
Purpose of the Study:
- To investigate an alternative signaling pathway for intercellular apoptosis induction.
- To identify mechanisms by which cancer cells might evade apoptosis.
- To explore the role of nitrite in apoptosis signaling.
Main Methods:
- Treatment of nontransformed fibroblasts with TGF-beta.
- Selective inhibition of signaling pathways using superoxide dismutase (SOD), terephthalate, aminobenzoyl hydrazide, and taurine.
- Assessment of apoptosis induction in transformed fibroblasts.
Main Results:
- A novel nitrite-dependent apoptosis signaling pathway was identified.
- This pathway remains effective when conventional pathways are blocked by SOD.
- Nitrite interacts with HOCl to form nitryl chloride, an apoptosis inducer.
- Nitrite-dependent apoptosis is inhibited by peroxidase and HOCl scavengers.
Conclusions:
- Nitryl chloride-mediated apoptosis is a significant finding in cancer research.
- This pathway may be crucial for inducing apoptosis in cancer cells that overexpress SOD.
- The discovery offers new insights into cancer cell death mechanisms and potential therapeutic targets.