NITRIC OXIDE-MEDIATED KYNURENINE/AHR SIGNALING ENHANCES DISEASE PROGRESSION IN PANCREATIC CANCER

Authors

• L Wang
• S Yang
• P He
• SP Hussain

Abstract

Pancreatic cancer is one of the most lethal malignancies and is the fourth leading cause of death due to cancer in the United States. The dismal prognosis in pancreatic cancer is due to the lack of early detection markers and its resistance to available treatments. Therefore, development of novel therapeutic target and treatment strategies are of utmost importance. We have recently shown that inducible nitric oxide synthase (NOS2)/NO• signaling enhances tumor progression and disease aggressiveness in pancreatic ductal adenocarcinoma (PDAC), which is the most common form of pancreatic cancer. Metabolic reprogramming is one of the hallmarks of cancer, and several metabolic adaptations are discovered in PDAC, which help pancreatic tumor cells to thrive under low nutrient and hypoxic condition. Therefore, metabolic vulnerabilities may be exploited to develop novel therapeutic strategies. Furthermore, inflammatory signaling pathways are implicated in regulating cellular metabolism. We hypothesized that NOS2/NO• signaling regulates metabolic reprogramming to enhance disease aggressiveness in PDAC. To test this hypothesis, we compared metabolic profile of tumors with NOS2-high and NOS2-low expression from resected human PDAC patients, and found that Kynurenine, a tryptophan metabolite, is associated with high NOS2 expression, and a higher level of Kynurenine is associated with poor survival in PDAC patients (N=69, p

Scientific Focus Area: Cancer Biology

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