Selective nitration of Hsp90 acts as a metabolic switch promoting tumor cell proliferation Journal Article


Authors: Logan, I. E.; Nguyen, K. T.; Chatterjee, T.; Manivannan, B.; Paul, N. P.; Kim, S. R.; Sixta, E. M.; Bastian, L. P.; Marean-Reardon, C.; Karajannis, M. A.; Fernández-Valle, C.; Estevez, A. G.; Franco, M. C.
Article Title: Selective nitration of Hsp90 acts as a metabolic switch promoting tumor cell proliferation
Abstract: Tumors develop in an oxidative environment characterized by peroxynitrite production and downstream protein tyrosine (Y) nitration. We showed that tyrosine nitration supports schwannoma cell proliferation and regulates cell metabolism in the inheritable tumor disorder NF2-related Schwannomatosis (NF2-SWN). Here, we identified the chaperone Heat shock protein 90 (Hsp90) as the first nitrated protein that acts as a metabolic switch to promote schwannoma cell proliferation. Doubling the endogenous levels of nitrated Hsp90 in schwannoma cells or supplementing nitrated Hsp90 into normal Schwann cells increased their proliferation. Metabolically, nitration on either Y33 or Y56 conferred Hsp90 distinct functions; nitration at Y33 (Hsp90NY33) down-regulated mitochondrial oxidative phosphorylation, while nitration at Y56 (Hsp90NY56) increased glycolysis by activating the purinergic receptor P2X7 in both schwannoma and normal Schwann cells. Hsp90NY33 and Hsp90NY56 showed differential subcellular and spatial distribution corresponding with their metabolic and proliferative functions in schwannoma three-dimensional cell culture models. Collectively, these results underscore the role of tyrosine nitration as a post-translational modification regulating critical cellular processes. Nitrated proteins, particularly nitrated Hsp90, emerge as a novel category of tumor-directed therapeutic targets. © 2024 The Authors
Keywords: controlled study; human tissue; protein expression; protein phosphorylation; human cell; cell proliferation; metabolism; neurofibromatosis; confocal microscopy; immunocytochemistry; western blotting; tumor cell; immunoblotting; heat shock protein 90; schwann cell; tumor; pheochromocytoma; oxygen consumption; cell metabolism; glycolysis; oxidative phosphorylation; neurilemoma; nerve degeneration; hsp90; mitochondrial respiration; nitration; human; article; p2x7 receptor; three dimensional cell culture; tyrosine nitration; mts assay; neurofibromatosis type 3
Journal Title: Redox Biology
Volume: 75
ISSN: 2213-2317
Publisher: Elsevier BV  
Date Published: 2024-09-01
Start Page: 103249
Language: English
DOI: 10.1016/j.redox.2024.103249
PROVIDER: scopus
PMCID: PMC11261529
PUBMED: 38945076
DOI/URL:
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus
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