The Contribution of redox regulation in tumor angiogenesis and tumor growth: glutathione peroxidase 4 (GPx4) as a key regulator of 12/15-lipoxygenase activity
Zusammenfassung der Projektergebnisse
Conflicting reports on the role of lipid hydroperoxides and reactive oxygen species (ROS) in cancer biology most likely reflect the use of different experimental systems and indicate the lack of appropriate transgenic mouse models for endogenous lipid peroxides/ROS to study the underlying mechanisms. Therefore, we took advantage of mouse models with genetic ablation of key redox-regulating enzymes and studied the impact of increased lipid peroxidation (deletion of glutathione peroxidase 4 (GPx4)) and/or enhanced mitochondrial hydrogen peroxide (H2O2) production (deletion of thioredoxin reductase 2 (Txnrd2)) on tumor growth and tumor-derived angiogenesis. Using mice and cells with an inducible disruption of GPx4, which is emerging as one of the most important glutathione-dependent enzymes, we could show that 12/15-lipoxygenase (12/15-LOX) is a specific downstream target of GPx4, thereby linking redox regulation, receptor tyrosine kinase signaling and arachidonic acid metabolism. Inducible endothelial-cell specific loss of GPx4 allowed us to demonstrate that the function of GPx4 in the endothelium can be fully substituted by adequate dietary vitamin E content. In contrast, combined deficiencies in GPx4 and dietary vitamin E resulted in multi-organ thrombus formation and lethality, thus pointing to a close cooperation of enzymatic and non-enzymatic antioxidant systems in the maintenance of vascular integrity. Our in vivo and in vitro models of genetic Txnrd2 ablation enabled us to unveil how the chronic generation of mitochondrial H2O2 impacts on HIF signaling and tumor growth via a novel signaling pathway. The cornerstones of this pathway encompass ROS-dependent activation of JNK, probably through the inhibition of JNK phosphatases, higher PHD2 protein levels, increased HIF-1α destabilization and decreased VEGF-A levels, all culminating in a delayed angiogenic switch, less pronounced tumor vascularization and, ultimately, reduced tumor growth.
