Extracellular Superoxide Anion Generation and Expression of Membrane-associated Catalase During Tumor Progression: Dynamic Interplay and Consequences for Tumor Cell Survival

Oncogenic transformation depends on the activation of membrane-associated NADPH oxidase. The resultant extracellular superoxide anions and H₂O₂ 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 signaling 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 signaling through oxidation of NO and decomposition of peroxynitrite. Therefore bona fide tumor cells regularly express a substantial concentration of membrane-associated catalase. As catalase is inhibited by superoxide anions, optimal catalase-mediated protection against intercellular apoptosis signaling requires the colocalization of SOD.

NOX1-derived superoxide anions/H₂O₂ control the expression of membrane-associated catalase in a dynamic mode. Inhibition of NOX1 therefore causes a dramatic decrease in the concentration of protective catalase and in parallel interferes with the stimulation of tumor cell proliferation leading to a state that resembles tumor cell dormancy.

Whereas nontransformed cells do not express sustained NOX1 activity, transformed cells, tumor cells and metastatic cells are characterized by strong NOX1 activity that increases with their stage related to tumor progression. The counterbalance by catalase is, however, not optimal at all stages.

Inhibition of membrane-associated catalase by neutralizing antibodies or its inactivation by exogenous or cell-derived singlet oxygen bears novel chances for therapy, based on reactivation of intercellular ROS signaling. Interestingly, a variety of natural plant compounds modulate the endogenous NO level in tumor cells and thus trigger the onset of an amplificatory pathway that culminates in extracellular singlet oxygen generation, catalase inactivation and tumor cell apoptosis.