REDOX SIGNALLING IN THE PANCREAS IN HEALTH AND DISEASE

This review addresses oxidative stress and redox signaling in the pancreas under physiological conditions as well as in acute pancreatitis, chronic pancreatitis, pancreatic cancer, and diabetes. Physiological redox homeodynamics is maintained mainly by NRF2/KEAP1, NF-κB, protein tyrosine phosphatases, peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α), and normal autophagy. Depletion of reduced glutathione in the pancreas is a hallmark of acute pancreatitis and is initially accompanied by disulfide stress, which is characterized by protein cysteinylation without increased glutathione oxidation. A cross-talk between oxidative stress, MAPKs, and NF-κB amplifies the inflammatory cascade, acting PP2A and PGC1α as key redox regulatory nodes. In acute pancreatitis, nitration of cystathionine-β synthase causes blockade of the trans-sulfuration pathway leading to increased homocysteine levels, whereas p53 triggers necroptosis in the pancreas through downregulation of sulfiredoxin, PGC1α, and peroxiredoxin 3. Chronic pancreatitis exhibits oxidative distress mediated by NADPH oxidase 1 and/or CYP2E1, which promotes cell death, fibrosis, and inflammation. Oxidative stress cooperates with mutant KRAS to initiate and promote pancreatic adenocarcinoma. Mutant KRAS increases mitochondrial ROS, which trigger acinar-to-ductal metaplasia and progression to PanIN. ROS are maintained at sufficient level to promote cell proliferation, whilst avoiding cell death or senescence through formation of NADPH and GSH, and activation of NRF-2, HIF-1/2α, and CREB. Redox signalling also plays a fundamental role in differentiation, proliferation, and insulin secretion of β-cells. However, ROS overproduction promotes β-cell dysfunction and apoptosis in type 1 and type 2 diabetes.