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

in Redox biology by Isabelle E Logan, Kyle T Nguyen, Tilottama Chatterjee, Bhagyashree Manivannan, Ngozi P Paul, Sharon R Kim, Evelyn M Sixta, Lydia P Bastian, Carrie Marean-Reardon, Matthias A Karajannis, Cristina Fernández-Valle, Alvaro G Estevez, Maria Clara Franco

TLDR

  • The study found that a protein called Heat shock protein 90 (Hsp90) is nitrated in schwannoma cells, which helps them proliferate and changes their metabolism. The study also found that nitrated Hsp90 is a potential target for new treatments for schwannoma.

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 (Hsp90) down-regulated mitochondrial oxidative phosphorylation, while nitration at Y56 (Hsp90) increased glycolysis by activating the purinergic receptor P2X7 in both schwannoma and normal Schwann cells. Hsp90and Hsp90showed 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.

Overview

  • The study investigates the role of tyrosine nitration in schwannoma cell proliferation and metabolism in the inherited tumor disorder NF2-related Schwannomatosis (NF2-SWN).
  • The methodology used for the experiment includes identifying 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 down-regulated mitochondrial oxidative phosphorylation, while nitration at Y56 increased glycolysis by activating the purinergic receptor P2X7 in both schwannoma and normal Schwann cells. Hsp90 and Hsp90 showed differential subcellular and spatial distribution corresponding with their metabolic and proliferative functions in schwannoma three-dimensional cell culture models. The primary objective of the study is to understand the role of tyrosine nitration in schwannoma cell proliferation and metabolism and identify nitrated proteins as a novel category of tumor-directed therapeutic targets.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions, including identifying 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 down-regulated mitochondrial oxidative phosphorylation, while nitration at Y56 increased glycolysis by activating the purinergic receptor P2X7 in both schwannoma and normal Schwann cells. Hsp90 and Hsp90 showed differential subcellular and spatial distribution corresponding with their metabolic and proliferative functions in schwannoma three-dimensional cell culture models. The key findings of the study are that tyrosine nitration supports schwannoma cell proliferation and regulates cell metabolism in the inherited tumor disorder NF2-SWN. Nitrated proteins, particularly nitrated Hsp90, emerge as a novel category of tumor-directed therapeutic targets.

Implications and Future Directions

  • The study's findings have significant implications for the field of research or clinical practice, as they underscore the role of tyrosine nitration as a post-translational modification regulating critical cellular processes. The study identifies the chaperone Heat shock protein 90 (Hsp90) as the first nitrated protein that acts as a metabolic switch to promote schwannoma cell proliferation. The study also shows that nitration on either Y33 or Y56 conferred Hsp90 distinct functions; nitration at Y33 down-regulated mitochondrial oxidative phosphorylation, while nitration at Y56 increased glycolysis by activating the purinergic receptor P2X7 in both schwannoma and normal Schwann cells. The study suggests that nitrated proteins, particularly nitrated Hsp90, emerge as a novel category of tumor-directed therapeutic targets. Future research directions could build on the results of the study, explore unresolved questions, or utilize novel approaches to further understand the role of tyrosine nitration in schwannoma cell proliferation and metabolism.
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