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

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.

Salivary MMP-9 as a Biomarker for the Diagnosis of Oral Potentially Malignant Disorders and Oral Squamous Cell Carcinoma.

OBJECTIVE: To compare the salivary MMP - 9 concentration among subjects with oral squamous cell carcinoma (OSCC), oral potentially malignant disorders (OPMD), tobacco users, and control groups. MATERIALS AND METHODS: A total of 88 subjects were enrolled and divided into four study groups viz., OSCC (n=24), OPMD (n=20), tobacco habits (n=22), and healthy controls (n=22). All subjects gave unstimulated saliva samples for the evaluation MMP - 9 by ELISA kit. Demographic information like age, gender, type of tobacco, and duration of the habit were recorded. RESULTS: Subjects with OSCC and OPMD had significantly higher mean MMP-9 levels than subjects with tobacco habits and control groups (P<0.001). Also, poorly differentiated OSCC group had significantly higher mean saliva MMP-9 than moderate and well-differentiated OSCC. The optimal cut-off point was 214.37 ng/mL with a sensitivity of 100% and specificity of 59% for OSCC versus the control group. The optimal cut-off point was as 205.87 ng/mL with a sensitivity of 100% and a specificity of 54% for OPMD versus the control group. CONCLUSION: The data obtained from this study indicated that OSCC and OPMD had an increased level of salivary MMP-9. Salivary MMP-9 could be a useful, non-invasive adjunct technique in the diagnosis, treatment, and follow-up of OSCC and OPMD. 
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