Expression of type 2 nitric oxide synthase and p21 in oral squamous cell carcinoma

Abstract

Nitric oxide (NO) has a complex role in tumour biology. Most cancer research has focused on the enzyme nitric oxide synthase-2 (NOS2), an inducible isoform responsible for prolonged NO production. In normal cells exposed to high NO concentrations, the tumour-suppressor gene, p53, promotes apoptosis via the p21 pathway, in an attempt to safeguard against potential NO-mediated DNA damage. In cancer cells with mutant p53, this pathway is unlikely to occur directly, although, p53-independent p21 expression and subsequent apoptosis can occur at higher NO concentrations. In this study, the possible direct association between NOS2 and p21 was assessed in oral squamous cell carcinoma. Immunohistochemistry was performed for NOS2 and p21 on 56 cases, and NOS2 activity was determined with citrulline assays in selected cases. A significant relationship was demonstrated between the immunohistochemical expression of NOS2 and its activity (P<0.001), but not between NOS2 and p21 expression (P=0.76). It is unlikely that the NO concentrations found in oral cancer (up to 10.3 pmol NO min(-1) mg protein(-1)) are sufficient to cause direct (p53-independent) p21 accumulation and subsequent apoptosis. As with many other tumours, since NO production has a detrimental role, its pharmacological inhibition in oral cancer represents an exciting area for possible future therapeutic manipulation.