Tyrosine nitration induces a metabolic reprogramming in neurofibromatosis type 2-associated Schwannoma cells

Neurofibromatosis type 2 (NF2) is a genetic tumor disorder of the nervous system caused by inactivation of the merlin tumor suppressor gene. The hallmark of the disease is the development of schwannomas along the acoustic nerve, and multiple other tumors for which there is no effective treatment. Production of peroxynitrite and subsequent tyrosine (Tyr) nitration of proteins occurs in multiple tumor types. However, the role of Tyr nitration in tumorigenesis is unknown. We showed that schwannomas from NF2 patients and merlin-deficient (MD)-Schwann cells (NF2-associated schwannoma cell culture models) have significantly increased levels of Tyr nitration compared to wild-type (WT) Schwann cells. Further, prevention of tyrosine nitration significantly and selectively decreases MD-Schwann cell survival. Here we show that endogenous tyrosine nitration induces a metabolic reprogramming in human MD-Schwann cells characterized by: 1) decreased oxidative phosphorylation activity due to cytochrome c oxidase inhibition, 2) increased glycolysis, and 3) almost complete glutamine dependency. Prevention of Tyr nitration reversed the metabolic phenotype of MD-Schwann cells back to that of WT-Schwann cells. We demonstrated that nitration of the chaperone Heat shock protein 90 (Hsp90) in tumor cells decreases mitochondrial metabolism. We show here that the intracellular delivery of nitrated Hsp90 in WT-Schwann cells significantly decreases mitochondrial oxygen consumption to levels comparable to those of MD-Schwann cells containing endogenous nitrated Hsp90. These observations suggest that nitrated Hsp90 participates in the metabolic reprogramming of MD-Schwann cells. Importantly, Hsp90 is not nitrated in any normal nervous tissue we have tested so far; implying that the nitrated form of Hsp90 could be an exceptional tumor-directed target for NF2 treatment in the short term. The identification of additional nitrated proteins that promote schwannoma metabolic reprogramming and growth could provide novel targets for the treatment of NF2 and potentially other tumor associated disorders. Supported by DoD, NRP, W81XWH-17-1-0409 (to MCF).