Targeting eNOS in Pancreatic Cancer

Abstract

Mortality from pancreatic ductal adenocarcinoma cancer (PDAC) is among the highest of any cancer and frontline therapy has changed little in years. Activation of endothelial nitric oxide synthase (eNOS or NOS III) has been implicated recently in the pathogenesis of PDAC. In this study, we used genetically engineered mouse and human xenograft models to evaluate the consequences of targeting eNOS in PDAC. Genetic deficiency in eNOS limited the development of pre-invasive pancreatic lesions and trended towards an extended lifespan in mice with advanced pancreatic cancer. These effects were also observed upon oral administration of the clinically evaluated NOS small molecule inhibitor L-NAME. Similarly, other transgenic models of oncogenic KRas-driven tumors responded to L-NAME treatment. Finally, these results were recapitulated in xenograft models of human pancreatic cancer, in which L-NAME was found to broadly inhibit tumorigenic growth. Taken together, our findings offer preclinical proof-of-principle to repurpose L-NAME for clinical investigations in treatment of PDAC and possibly other KRas-driven human cancers.

Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer

“…As mentioned earlier, NOSTRIN has been described to bind eNOS and modulates its intracellular distribution and reduces the release of NO. Additionally, eNOS-generated NO may contribute to the development and progression of pancreatic cancer (21). Therefore, we tested the hypothesis that NOSTRIN-induced suppression of pancreatic cancer cell migration and invasion is mediated through the inhibition of eNOS and subsequent reduction in NO level.…”

“…NO is generated during the conversion of arginine to citruline, a reaction catalyzed by a family of nitric oxide synthases (NOS), which includes neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). Both iNOS and eNOS are implicated in the development and progression of pancreatic cancer (21, 29, 30). In a recent study, genetic and pharmacological inhibition of eNOS resulted in reduced tumorigenesis in a genetically engineered mouse model of PDAC (21).…”

“…Both iNOS and eNOS are implicated in the development and progression of pancreatic cancer (21, 29, 30). In a recent study, genetic and pharmacological inhibition of eNOS resulted in reduced tumorigenesis in a genetically engineered mouse model of PDAC (21). eNOS activity is regulated through phosphorylation in addition to the calcium concentration, and phosphorylated eNOS (p-eNOS) can produce a high and sustained level of NO (22, 31).…”

AMPK and Endothelial Nitric Oxide Synthase Signaling Regulates K-Ras Plasma Membrane Interactions via Cyclic GMP-Dependent Protein Kinase 2

“…Conversely, Counter and colleagues reported that elevated eNOS activity contributes to the development of K-Ras-driven pancreatic ductal adenocarcinomas (PDACs) (63). Advanced PDACs with an induced genetic deficiency of eNOS or treatment of mice with a NOS inhibitor limited the development of preinvasive pancreatic lesions and somewhat extended the mouse life span (63).…”

“…Advanced PDACs with an induced genetic deficiency of eNOS or treatment of mice with a NOS inhibitor limited the development of preinvasive pancreatic lesions and somewhat extended the mouse life span (63). It is therefore tempting to speculate that in different .…”