| First Author | Hu CM | Year | 2019 |
| Journal | Cell Metab | Volume | 29 |
| Issue | 6 | Pages | 1334-1349.e10 |
| PubMed ID | 30853214 | Mgi Jnum | J:275999 |
| Mgi Id | MGI:6313681 | Doi | 10.1016/j.cmet.2019.02.005 |
| Citation | Hu CM, et al. (2019) High Glucose Triggers Nucleotide Imbalance through O-GlcNAcylation of Key Enzymes and Induces KRAS Mutation in Pancreatic Cells. Cell Metab 29(6):1334-1349.e10 |
| abstractText | KRAS mutations are the earliest events found in approximately 90% of pancreatic ductal adenocarcinomas (PDACs). However, little is known as to why KRAS mutations preferentially occur in PDACs and what processes/factors generate these mutations. While abnormal carbohydrate metabolism is associated with a high risk of pancreatic cancer, it remains elusive whether a direct relationship between KRAS mutations and sugar metabolism exists. Here, we show that under high-glucose conditions, cellular O-GlcNAcylation is significantly elevated in pancreatic cells that exhibit lower phosphofructokinase (PFK) activity than other cell types. This post-translational modification specifically compromises the ribonucleotide reductase (RNR) activity, leading to deficiency in dNTP pools, genomic DNA alterations with KRAS mutations, and cellular transformation. These results establish a mechanistic link between a perturbed sugar metabolism and genomic instability that induces de novo oncogenic KRAS mutations preferentially in pancreatic cells. |
