NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions - PubMed
4 hours ago
- #Oxidative Stress
- #NADPH
- #Pancreatic Cancer
- Acinar-to-ductal metaplasia (ADM) is a reversible cell state that aids pancreas repair after injury, but oncogenic KRAS mutations can progress it to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC).
- Global changes in central carbon metabolism genes and metabolites occur during ADM formation, with significant induction of NRF2-target genes, including NADPH-producing enzymes like glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1), which regulate oxidative stress.
- In mouse models, deficiency in G6PD or ME1 increases reactive oxygen species and lipid peroxidation, accelerating the formation of ADM and PanIN lesions, while ME1 loss specifically promotes faster PDAC progression.
- Oxidative stress is necessary for ADM progression, as pharmacological antioxidant treatment attenuates ADM in vivo and ex vivo, whereas depleting the antioxidant glutathione promotes precancerous lesions in human acinar cells and mice, highlighting the role of metabolic reprogramming in early pancreatic tumorigenesis.