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.
Subject(s)
Neoplastic Syndromes, Hereditary/genetics , Neoplastic Syndromes, Hereditary/pathology , Skin Diseases, Papulosquamous/pathology , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Tumor Suppressor Proteins/genetics , Biopsy, Needle , Deubiquitinating Enzyme CYLD , Diagnosis, Differential , Facial Dermatoses/genetics , Facial Dermatoses/pathology , Facial Dermatoses/therapy , Female , Gene Expression Regulation , Humans , Middle Aged , Mutation , Neoplastic Syndromes, Hereditary/therapy , Rare Diseases , Scalp Dermatoses/genetics , Scalp Dermatoses/pathology , Scalp Dermatoses/therapy , Skin Diseases, Papulosquamous/diagnosis , Skin Diseases, Papulosquamous/therapy , Skin Neoplasms/therapy , Teaching RoundsABSTRACT
INTRODUCTION: Varicella zoster virus is a highly contagious virus that causes a primary infection known as varicella (chickenpox) that may reactivate years later to cause herpes zoster (HZ or shingles). After shingles heal, patients may develop post-herpetic neuralgia (PHN), neuropathic pain syndrome that can cause significant suffering for years and is often refractory to treatment. AREAS COVERED: The wide range of treatment and management options for varicella, HZ and PHN are reviewed and discussed. PubMed was the database used for the literature search. EXPERT OPINION: Antiviral therapy effectively treats acute varicella and HZ. However, PHN is still difficult to manage, especially with the numerous treatment measures that do not work consistently in all patients. The best approach is to prevent the complication from occurring in the first place by preventing HZ with the HZ vaccine, which have decreased the burden of illness caused by VZ and the incidence of HZ. Unlike the varicella vaccine, the uptake for the HZ vaccine is very low and thereby more patients over the age of 50 years should be encouraged to receive the vaccine to reduce the risk of developing HZ. Initiating treatment with gabapentin and antiviral concomitantly as soon as the rash develops may reduce the severity of complications but there is a lack of data showing these medications preventing the development of PHN.
