NO• and Pancreatic Cancer: A Complex Interaction with Therapeutic Potential

Abstract

Significance: Pancreatic tumors express high level of nitric oxide synthases (NOSs) in particular inducible (iNOS/NOS2) and endothelial (eNOS/NOS3) forms. However, the role of nitric oxide (NO^•) in the development and progression of pancreatic cancer is not clearly defined. Delineating the NO^•-induced signaling in pancreatic cancer and its potential contribution in disease aggressiveness may provide therapeutic targets to improve survival in this lethal malignancy. Recent Advances: An increased expression of NOS2/iNOS in tumors is associated with poorer survival in early stage resected patients with pancreatic ductal adenocarcinoma (PDAC). Furthermore, genetic deletion of NOS2 enhanced survival in mice with autochthonous PDAC. Additionally, targeting NOS3/eNOS reduced the abundance of precursor lesions in mice, which trended toward improved survival.

Critical issues: The extremely poor prognosis in pancreatic cancer is due to the late diagnosis and lack of effective therapy in advanced disease. One of the most critical issues is to decipher the underlying mechanism of disease aggressiveness and therapeutic resistance for identifying potential therapeutic target and effective treatment. Given the evidence of a strong association between inflammation and pancreatic cancer and clinical evidence, which suggests an association between NOS2 and disease aggressiveness, it is critical to define the role of NO^• signaling in this lethal malignancy.

Future directions: Recent preclinical and clinical evidences indicate a potential therapeutic significance of targeting NO^• signaling in pancreatic cancer. With the emergence of new preclinical models, including the patient-derived organoids, further preclinical evaluation using clinically tested NOS inhibitors is needed for designing future clinical investigation. Antioxid. Redox Signal. 26, 1000-1008.

Keywords: Nostrin; microRNA; nitric oxide; nitric oxide synthase; pancreatic cancer; pancreatic ductal adenocarcinoma (PDAC).

FIG. 1.

Schematic representation of a brief history suggesting a role of NO^• in the development and progression of pancreatic cancer. NO^•, nitric oxide. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Protumorigenic role of NOS2 and NOS3 based on the studies involving genetically engineered mouse model of pancreatic cancer with pancreas-specific mutation in the Kras and P53 genes. eNOS/NOS3, endothelial nitric oxide synthase; iNOS/NOS2, inducible nitric oxide synthase. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

NOSTRIN is a predictor of prognosis in early stage resected patients with PDAC. Patients with a higher NOSTRIN expression in tumors survive longer compared with patients with a lower expression of NOSTRIN. NOSTRIN inhibits NOS3 (eNOS) and reduces NO production. NOSTRIN, endothelial nitric oxide synthase traffic inducer; PDAC, pancreatic ductal adenocarcinoma. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

The principal source of a high and sustained level of NO^• is the NOS2. However, NO^• produced by NOS2 and NOS3 is implicated in pancreatic cancer progression. NO^• signaling is reported to have both pro- and antitumorigenic functions. Further mechanistic, functional, preclinical, and clinical studies are warranted to guide the potential therapeutic benefits of NO^•-based or NO^•-targeted treatment strategies. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars