期刊
CELL METABOLISM
卷 29, 期 6, 页码 1334-+出版社
CELL PRESS
DOI: 10.1016/j.cmet.2019.02.005
关键词
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资金
- Academia Sinica grants from the Ministry of Science and Technology, Taiwan [MOST 104-0210-01-09-02, MOST 105-0210-01-13-01, MOST 106-0210-01-15-02]
- higher-education sprout project by the Ministry of Education, Taiwan
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.
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