The Potential Role of iNOS in Ovarian Cancer Progression and Chemoresistance

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.

Keywords: chemoresistance; iNOS; ovarian cancer.

Figure 1

Domain-structured scheme of iNOS monomer. iNOS monomer is composed of oxygen domain that associates L-arginine (L-ARG), protoporphyrin IX (HEME) and tetrahydropterin (BH4), as well as reductase domain that consists of flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD) and reduced form of nicotinamide adenine dinucleotide phosphate (NADPH). Calmodulin (CaM) is noncovalently bound to the iNOS complex.

Figure 2

Regulation of iNOS expression in ovarian cancer microenvironment. Factors present in the ovarian cancer microenvironment, such as proinflammatory cytokines (IL-1β, IL-6, TNF-α), as well as hypoxia and overactivation of some signaling pathways (e.g., JAK/STAT3, AKT/PI3K, MAPKs), are responsible for upregulation of iNOS expression in tumor cells, while agents like TGF-β1 and arginase downregulate its expression.

Figure 3

Role of NO and reactive nitrogen species in tumorigenesis. Although the role of iNOS has never been directly determined in carcinogenesis, the activity of its product—nitric oxide (NO)—and NO’s derivatives, such as peroxynitrite (ONOO⁻) or dinitrogen trioxide (N₂O₃), influence normal cells causing their transformation and inducing tumorigenesis. BER, base extinction repair system; G, guanine; A, adenosine; C, cytosine; U, uracil; T, thymidine.

Figure 4

Selected mechanisms of NO/RNS impact on cisplatin resistance in cancer cells. RNS, reactive nitrogen species; STAT3, signal transducer and activator or transcription pathways 3; AKT, serine-threonine protein kinase.