Abstract
Inducible nitric oxide synthase (iNOS), the enzyme responsible for nitric oxide (NO) production, is not present in most cells under normal conditions. The expression of its mRNA, as well as its protein synthesis and full enzymatic activity, undergoes multilevel regulation including transcriptional and posttranscriptional mechanisms, the availability of iNOS substrate and cofactors and oxygen tension. However, in various malignant diseases, such as ovarian cancer, the intracellular mechanisms controlling iNOS are dysregulated, resulting in the permanent induction of iNOS expression and activation. The present review summarizes the multistaged processes occurring in normal cells that promote NO synthesis and focuses on factors regulating iNOS expression in ovarian cancer. The possible involvement of iNOS in the chemoresistance of ovarian cancer and its potential as a prognostic/predictive factor in the course of disease development are also reviewed. According to the available yet limited data, it is difficult to draw unequivocal conclusions on the pros and cons of iNOS in ovarian cancer. Most clinical data support the hypothesis that high levels of iNOS expression in ovarian tumors are associated with a greater risk of disease relapse and patient death. However, in vitro studies with various ovarian cancer cell lines indicate a correlation between a high level of iNOS expression and sensitivity to cisplatin.
Highlights
Inducible nitric oxide synthase is one of three isoforms belonging to the family of nitric oxide synthases, which are enzymes that catalyze the production of nitric oxide (NO) from L-arginine. iNOS is a unique enzyme since the iNOS transcript and protein are not present under normal conditions in most cells
While the importance of iNOS expression in ovarian tumors is not obvious and far from being fully understood, the present review summarizes its possible involvement in the development and growth of ovarian cancer, its association with the chemoresistance of ovarian cancer cells to platinum compounds, and its potential as a prognostic factor in the course of this disease
Very interesting and widely ranging studies were completed by Anttila et al [65]. iNOS expression was tested in specimens from 301 epithelial ovarian cancer patients with consideration to FIGO stage, histopathological type, and histological grade. iNOS expression was correlated with histological subtype, and high levels of iNOS expression were only found in mucinous tumors
Summary
Inducible nitric oxide synthase (iNOS, NOS2) is one of three isoforms belonging to the family of nitric oxide synthases, which are enzymes that catalyze the production of nitric oxide (NO) from L-arginine. iNOS is a unique enzyme since the iNOS transcript and protein are not present under normal conditions in most cells. MMoonnoommeerriicc iiNNOOSS iiss uunnaabbllee ttoo bbiinndd tthhee BBHH44 ccooffaaccttoorr aanndd tthhee LL--aarrggiinniinnee ssuubbssttrraattee,, tthhuuss,, iitt ccaannnnoott ssyynntthheessiizzee nniittrriicc ooxxiiddee. Transforming growth factor-β1 (TGF-β1) and antioxidants inhibit NF-κB activity through the induction of its ubiquitin-dependent proteasomal degradation, blocking its translocation to the nucleus or enhancing I-κB expression [5,11,12,13]. MiR-939 binding decreased cytokine-induced iNOS protein expression but did not affect its mRNA level and stability. The expression of iNOS in tumor cells is upregulated (Figure 2) by extracellular signals, such as pro-inflammatory cytokines and hypoxia. The ovarian cancer tumor microenvironment is characterized by high levels of IL-6, IL-1, and TNF-α, which strongly activate the JAK/STAT and MAPK signaling pathways known to be iNOS inducers [31,32]. The NO/ effect of NO/RNS on DNA should be considered only as one of many possible mechanisms
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