Abstract
Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder characterized by the development of bilateral vestibular schwannomas. The NF2 gene encodes the tumor suppressor merlin, and loss of merlin activity promotes tumorigenesis and causes NF2. Cellular redox signaling has been implicated in different stages of tumor development. Among reactive nitrogen species, peroxynitrite is the most powerful oxidant produced by cells. We recently showed that peroxynitrite-mediated tyrosine nitration down-regulates mitochondrial metabolism in tumor cells. However, whether peroxynitrite supports a metabolic shift that could be exploited for therapeutic development is unknown. Here, we show that vestibular schwannomas from NF2 patients and human, merlin-deficient (MD) Schwann cells have high levels of endogenous tyrosine nitration, indicating production of peroxynitrite. Furthermore, scavenging or inhibiting peroxynitrite formation significantly and selectively decreased survival of human and mouse MD-Schwann cells. Using multiple complementary methods, we also found that merlin deficiency leads to a reprogramming of energy metabolism characterized by a peroxynitrite-dependent decrease of oxidative phosphorylation and increased glycolysis and glutaminolysis. In MD-Schwann cells, scavenging of peroxynitrite increased mitochondrial oxygen consumption and membrane potential, mediated by the up-regulation of the levels and activity of mitochondrial complex IV. This increase in mitochondrial activity correlated with a decrease in the glycolytic rate and glutamine dependence. This is the first demonstration of a peroxynitrite-dependent reprogramming of energy metabolism in tumor cells. Oxidized proteins constitute a novel target for therapeutic development not only for the treatment of NF2 schwannomas but also other tumors in which peroxynitrite plays a regulatory role.
Highlights
Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder characterized by the development of bilateral vestibular schwannomas
The increase in NOS expression correlated with a decrease in the expression of the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) (Fig. 1F), suggesting that the loss of merlin expression induces an increase in peroxynitrite formation by increasing nitric oxide production while decreasing superoxide clearance by MnSOD in NF2 schwannoma cells
We show that the metabolic reprogramming of NF2 schwannoma cells is tightly regulated by peroxynitrite, suggesting that novel therapeutic targets for NF2 treatment could be identified among oxidized proteins
Summary
Dept. of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065. lism in tumor cells. In tumor cells nitration of Hsp on tyrosine 33 but not 56 down-regulates mitochondrial activity through the formation of a protein complex, suggesting that differential nitration states of Hsp regulate distinct aspects of cell metabolism [29] These observations provide strong evidence for a role of peroxynitrite in regulating key molecular processes involved in pathology. Scavenging peroxynitrite-derived radicals with urate reverted the metabolic phenotype of human MD-Schwann cells back to that of isogenic WT-Schwann cells at least in part by increasing the levels and activity of the cytochrome c oxidase (complex IV) Together these observations reveal that peroxynitrite plays an important role in the regulation of the metabolic phenotype of NF2 schwannoma cells. Proteins oxidized by peroxynitrite could be exceptional targets for the development of tumor-directed therapies for the treatment of NF2 and possibly for treatment of other solid tumors
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