5 years ago

HOCl and the control of oncogenesis

HOCl and the control of oncogenesis
Sustained generation of extracellular superoxide anions by membrane-associated NADPH oxidase-1 is a hallmark of malignant transformation. The resulting H2O2 drives the proliferation of malignant cells and is converted to HOCl by a Dual oxidase-related peroxidase domain that acts analogously to myeloperoxidase. Whereas H2O2 induces apoptosis nonselectively in nontransformed and transformed cells, HOCl selectively affects malignant cells, as the interaction between HOCl and extracellular superoxide anions allows for site-specific generation of apoptosis-inducing hydroxyl radicals. Transformed cells (early stages of tumor progression) and bona fide tumor cells (representing late stages of tumor progression) respond to exogenous HOCl or HOCl generated by professional phagocytes with induction of apoptosis. In contrast, only transformed cells have the potential to synthesize HOCl through interaction between their superoxide anions/H2O2 and Dual oxidase-related peroxidase released by themselves or neighbouring nontransformed or transformed effector cells. Tumor cells prevent HOCl synthesis through membrane-associated catalase that decomposes H2O2, the substrate for peroxidase, and thus prevents HOCl synthesis. Elimination of malignant cells through HOCl signaling is prevented by Helicobacter pylori-associated catalase and superoxide dismutase, whereas it is enhanced by low dose irradiation and by H2O2-producing lactobacilli in the presence of myeloperoxidase. Peroxidase and catalase that are involved in the control of HOCl signaling are also affecting apoptosis-inducing pathways based on reactive nitrogen species. Modification of tumor cell proteins by HOCl enhances the establishment of a T cell response and thus might be involved in immunogenic modulation. Therefore, targeting the control of HOCl signaling system should allow one to establish novel rational therapeutic approaches.

Publisher URL: www.sciencedirect.com/science

DOI: S0162013417303318

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