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Target cell-derived superoxide anions cause efficiency and selectivity of intercellular induction of apoptosis
M Herdener1, S Heigold, M Saran
1Abteilung Virologie, Institut für Medizinische Mikrobiologie und Hygiene, Universität Freiburg, Freiburg, Germany.
Abstract:
Transformed fibroblasts are specifically eliminated by their nontransformed neighbors through intercellular induction of apoptosis. This process depends on the number of nontransformed effector cells and on the local density of transformed target cells. Intercellular signalling is inhibited by SOD (a scavenger of superoxide anions), taurine (a scavenger of HOCl), 4-aminobenzoyl hydrazide (a mechanism-based inhibitor of peroxidase), DMSO (a hydroxyl radical scavenger), and two inhibitors of NO synthase. Therefore, selective apoptosis induction seems to be based on superoxide anion production by transformed cells, their spontaneous dismutation to hydrogen peroxide, and HOCl generation by a novel effector cell-derived peroxidase. HOCl then interacts with target cell-derived superoxide anions to yield hydroxyl radicals. Due to the short diffusion pathway of superoxide anions, hydroxyl radical generation is confined to the intimate vicinity of transformed cells. In parallel, NO derived from effector cells interacts with superoxide anions of target cells to yield the apoptosis inducer peroxynitrite. Reconstitution experiments using transformed or nontransformed cells in conjunction with myeloperoxidase, HOCl, or an NO donor demonstrated that superoxide anions generated extracellularly by transformed cells participate in intercellular signalling and at the same time determine transformed cells as selective targets for intercellular induction of apoptosis.
Insights
Nontransformed cells eliminate cancerous fibroblasts via apoptosis, a process involving superoxide anions and hydroxyl radicals. This targeted cell death mechanism relies on specific chemical signals between cells.
Area of Science:
- Cell Biology
- Biochemistry
- Cancer Research
Background:
- Nontransformed cells can eliminate transformed cells through apoptosis.
- This process is crucial for tissue homeostasis and tumor suppression.
- The precise molecular mechanisms underlying this selective elimination are not fully understood.
Purpose of the Study:
- To elucidate the molecular mechanisms by which nontransformed cells induce apoptosis in transformed fibroblasts.
- To identify the key reactive oxygen and nitrogen species involved in this intercellular signaling process.
- To determine the role of superoxide anions in targeting transformed cells for apoptosis.
Main Methods:
- Utilized coculture systems of transformed and nontransformed fibroblasts.
- Investigated the effect of various chemical inhibitors (SOD, taurine, 4-aminobenzoyl hydrazide, DMSO, NO synthase inhibitors) on apoptosis induction.
- Performed reconstitution experiments with purified components like myeloperoxidase, HOCl, and NO donors.
Main Results:
- Selective apoptosis induction was dependent on effector cell numbers and target cell density.
- Inhibitors of reactive oxygen and nitrogen species blocked intercellular signaling.
- Evidence suggests a mechanism involving superoxide anion production by transformed cells, hydrogen peroxide formation, HOCl generation by effector cells, and subsequent hydroxyl radical and peroxynitrite formation.
- Extracellular superoxide anions from transformed cells mediate signaling and target selection.
Conclusions:
- Intercellular apoptosis induction relies on a complex interplay of reactive oxygen and nitrogen species.
- Transformed cells generate superoxide anions that initiate a signaling cascade, marking them for elimination.
- This mechanism highlights a novel pathway for endogenous tumor suppression.