NO and COX2: Dual targeting for aggressive cancers.

A number of tumor-specific characteristics are known to associate with a cancer’s growth, metastatic potential, and response to therapy. Among these are mutational load and gene-expression patterns in the tumor cells and the interaction of the tumor cells with the many cellular and noncellular components that comprise the microenvironment of the tumor. One molecule that has received considerable attention in tumor biology is nitric oxide (NO), a shortlived locally acting but highly diffusible intraand intercellular signaling molecule (1, 2). This attention is well warranted because NO can regulate almost every process important to carcinogenesis, including DNA damage/repair, cell proliferation, blood flow/angiogenesis, cell migration and invasion, cell death and survival, inflammation, and immune responses (3). However, nearly three decades of intense mechanism-based research has yielded a large number of conflicting results on the even basic question of whether NO is proor antineoplastic (1). This has led many to conclude that the role of NO in tumor biology is highly context-dependent and determined by the sources of NO, the level and duration of NO production, and the background phenotype of the tumor. However, an emerging theme with some consistency in human cancers is that the expression of the high-output inducible NO synthase (iNOS or NOS2) associates with poor outcome in many solid and hematological malignancies. For example, NOS2 can act as a poor prognostic indicator for survival in many aggressive cancers, including glioblastoma, melanoma, pancreatic, liver, esophageal, gastric, cervical, ovarian, prostate, and lung adenocarcinoma, with hazard ratios (HR) greater than threefold in most of these cancers (4–9). Similarly, NOS2 has been shown to be a predictor of poor survival in estrogen receptornegative (ER) breast cancer patients (10), especially in the subset of highly aggressive chemoresistant metaplastic breast cancers (11). Although expression of NOS2 in human macrophages is limited compared with rodents, the expression of NOS2 in human epithelial cells can be robust, which lead to its initial cloning and characterization in human hepatocytes (12). This may explain, in part, its prevalence in aggressive human epithelial malignancies. Fig. 1. Chronic levels of NO promote inflammation and tumorigenesis. NO is primarily generated by NOS2 from the cancer cells; however, immune, endothelial and stromal cells also produce NO. In ER− breast cancer, NO production is driven by a NOS2/COX2 cross-talk. NO activates an inflammatory cascade that produces an up-regulation of COX2, increasing levels of PGE2. Similarly, PGE2 also promotes the synthesis of NOS2. Two different pathways (green) are commonly activated by NO: TNF-α/TRAF2//cJun/MAPK/COX2, and c-Src/PI3K/cJun/COX2. In Basal A Er− breast cancer cell lines (purple), NF-κβ is also involved in the activation of Fra1/cJun, causing COX2 activation. In aggressive Basal B subtype (gray), IRE1α promotes the activation of MAPK. COX2 activation phosphorylates pAKT S847 that inactivates proapoptotic BAD and CAS9 activation. Both NOS2 and COX2 activate the secretion of IL-8, IL-6, and GM-CSF to sustain tumor microenvironment. Other enzymes from NOX, COX, and LOX families also produce free radicals like NO, which translate in different signals such as tumor maintenance, proliferation, and survival. NOS2 (blue) and COX2 (yellow) co-overexpression is a risk factor for poor prognosis in ER− breast cancer patients (HR = 21.2, 95% CI: 2.78–161.9, P = 0.003).