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Synergistic Interactions Between Nitric Oxide And Reactive Oxygen Species Cause Selective Apoptosis Induction In
1Institute of Virology, Department of Medical Microbiology and Hygiene, University Medical Center, Freiburg, Germany.
Background:
Oncogenic transformation depends on the activation of membrane-associated NADPH oxidase. The resultant extracellular superoxide anions control the proliferation of malignant cells, but they also drive two intercellular signaling pathways that cause selective apoptosis induction in malignant cells, i. e. the HOCl and the NO/peroxynitrite pathway. Tumor progression requires the establishment of resistance against these apoptosis-inducing pathways through expression of membrane-associated catalase that interferes with HOCl signaling through decomposition of H2O2 and with NO/peroxynitrite through oxidation of NO and decomposition of peroxynitrite.
Aims:
We aimed to establish the biochemical basis for novel therapeutic approaches that target tumor cell protective catalase and thus cause reactivation of intercellular reactive oxygen/nitrogen species-dependent apoptotic signaling of tumor cells.
Methods:
We used cells from defined stages of multistep oncogenesis, i. e. nontransformed, transformed and bona vide tumor cells. Intercellular apoptosis-inducing ROS/RNS signaling was studied using defined inhibitors/scavengers, reconstitution experiments and small interfering RNA directed against relevant targets.
Results:
Direct inhibition of tumor cell catalase by neutralizing antibodies or its direct inactivation by extracellular singlet oxygen caused efficient reactivation of apoptosis-inducing signaling. Interestingly, the increase in cell-derived NO through addition of arginine, inhibition of arginase, inhibition of NO dioxygenase or induction of NO synthase by interferon led to the generation of extracellular singlet oxygen that triggered a complex self-amplificatory system. As a result, high concentrations of cell-derived singlet oxygen inactivated catalase and reactivated apoptosis inducing intercellular signaling.
Conclusions:
Modulation of the cellular NO concentration causes extracellular singlet oxygen generation and inactivation of tumor cell protective catalase.
Insights
Targeting tumor cell catalase can reactivate apoptosis-inducing signaling. Modulating nitric oxide (NO) levels generates singlet oxygen, which inactivates catalase, offering a novel therapeutic strategy against cancer by restoring reactive oxygen/nitrogen species signaling.
Area of Science:
- Biochemistry
- Cancer Biology
- Immunology
Background:
- Oncogenic transformation relies on NADPH oxidase, producing superoxide anions that influence malignant cell proliferation.
- Tumor cells develop resistance to apoptosis-inducing pathways (HOCl, NO/peroxynitrite) via membrane-associated catalase, which degrades H2O2 and oxidizes NO.
- Catalase protects tumors by interfering with reactive oxygen/nitrogen species (ROS/RNS)-dependent apoptosis signaling.
Purpose of the Study:
- To investigate novel therapeutic strategies targeting tumor cell catalase.
- To explore the reactivation of ROS/RNS-dependent apoptotic signaling in tumor cells by inhibiting catalase.
- To establish the biochemical basis for catalase-targeted cancer therapies.
Main Methods:
- Utilized cells across different oncogenesis stages (nontransformed, transformed, tumor cells).
- Investigated intercellular apoptosis-inducing ROS/RNS signaling using inhibitors, scavengers, and small interfering RNA (siRNA).
- Performed reconstitution experiments to validate signaling pathways.
Main Results:
- Direct catalase inhibition (antibodies, singlet oxygen) reactivated apoptosis-inducing signaling.
- Increased nitric oxide (NO) levels (arginine, arginase inhibition, NO synthase induction) generated extracellular singlet oxygen.
- Singlet oxygen inactivated catalase, leading to self-amplification and reactivation of apoptosis signaling.
Conclusions:
- Modulating cellular nitric oxide (NO) concentration is key to generating extracellular singlet oxygen.
- Extracellular singlet oxygen effectively inactivates tumor cell protective catalase.
- This mechanism offers a potential pathway for reactivating anti-tumor apoptosis signaling.
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