Selective nitration of Hsp90 acts as a metabolic switch promoting tumor cell proliferation
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
Affiliations
Isabelle E. Logan
Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA; Center for Translational Science, Florida International University, Florida, 34987, USA
Kyle T. Nguyen
Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA
Tilottama Chatterjee
Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA
Bhagyashree Manivannan
Center for Translational Science, Florida International University, Florida, 34987, USA
Ngozi P. Paul
Center for Translational Science, Florida International University, Florida, 34987, USA
Sharon R. Kim
Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA
Evelyn M. Sixta
Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA
Lydia P. Bastian
Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA
Carrie Marean-Reardon
Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA
Matthias A. Karajannis
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
Cristina Fernández-Valle
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, 32827, USA
Alvaro G. Estevez
Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA; Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Florida, 33199, USA
Maria Clara Franco
Department of Biochemistry and Biophysics, College of Science, Oregon State University, Corvallis, OR, 97331, USA; Center for Translational Science, Florida International University, Florida, 34987, USA; Department of Cellular and Molecular Medicine, Herbert Wertheim College of Medicine, Florida International University, Florida, 33199, USA; Corresponding author. 11350 SW Village Pkwy, Port St. Lucie, FL, 34987, USA.
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.
