Branched-chain amino acid catabolism is potentially deficient in pancreatic cancer with high-neural invasion

Abstract

Abstract Elevated plasma branched-chain amino acid (BCAA) levels are observed in some metabolic disorders, such as obesity and diabetes, due to impaired hepatic BCAA catabolism. In pancreatic cancer, elevated plasma BCAA levels are observed years before diagnosis, possibly due to increased protein degradation. However, the status of BCAA catabolism in pancreatic cancer remains unclear. Here, we hypothesized that defective hepatic BCAA utilization contributes to this elevation in pancreatic cancer, similar to observations in obesity and diabetes. Consistent with our hypothesis, increased phosphorylation of the hepatic BCAA catabolic enzyme, branched-chain α-keto acid dehydrogenase (BCKDH), was observed in a murine nerve invasion model with human pancreatic cancer cells, indicative of an inactive state. Notably, this was associated with reduced whole-body BCAA flux, increased skeletal muscle degradation, and elevated plasma BCAA levels. Patients with stage III pancreatic cancer with severe neural invasion exhibited high plasma BCAA and reduced muscle mass. In addition, patients with stage IV pancreatic cancer showed hepatic BCKDH phosphorylation, which correlated with poor prognosis. Overall, these results suggest the potential existence of impaired BCAA catabolism via hepatic BCKDH downregulation in pancreatic cancer.