High Glucose Triggers Nucleotide Imbalance through O-GlcNAcylation of Key Enzymes and Induces KRAS Mutation in Pancreatic Cells
Journal
Cell Metabolism
Journal Volume
29
Journal Issue
6
Pages
1334-13490000000000
Date Issued
2019
Author(s)
Hu C.-M.
Tien S.-C.
Hsieh P.-K.
Chen Y.-J.
Chen Y.-J.
Lee E.Y.-H.P.
Lee W.-H.
Abstract
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. Most pancreatic ductal adenocarcinomas contain activated KRAS mutations required for cancer initiation and maintenance. Here, Hu et al. show that high glucose promotes O-GlcNAcylation on ribonucleotide reductase, leading to nucleotide pool imbalance and KRAS mutations preferentially in pancreatic cells. ? 2019 Elsevier Inc.
SDGs
Other Subjects
6 phosphofructokinase; DNA; fructose bisphosphate aldolase; genomic DNA; glucose; glucose 6 phosphate dehydrogenase; glutamine; hemoglobin A1c; K ras protein; messenger RNA; nucleotide; ribonucleotide reductase; short hairpin RNA; acyltransferase; enzyme; glucose; KRAS protein, human; n acetylglucosamine; nucleotide; protein p21; acinar cell; acylation; animal cell; animal experiment; animal tissue; Article; binding affinity; body weight gain; cell growth assay; cell transformation; chow diet; colony formation; comparative study; controlled study; DNA damage; DNA repair; enzyme activity; fasting; genomic instability; glucose blood level; glucose transport; hemoglobin blood level; human; human tissue; immunoprecipitation; liquid chromatography-mass spectrometry; male; metabolic disorder; mouse; mutation; next generation sequencing; nonhuman; pancreas cell; priority journal; protein processing; Sanger sequencing; single nucleotide polymorphism; Western blotting; acetylation; adult; aged; animal; C57BL mouse; cell culture; dose response; drug effect; female; genetics; HEK293 cell line; metabolism; middle aged; mutagenesis; newborn; pancreas; pancreas carcinoma; pancreas tumor; pathology; young adult; Acetylation; Acetylglucosamine; Acetyltransferases; Adult; Aged; Animals; Carcinoma, Pancreatic Ductal; Cell Transformation, Neoplastic; Cells, Cultured; DNA Damage; Dose-Response Relationship, Drug; Enzymes; Female; Glucose; HEK293 Cells; Humans; Infant, Newborn; Male; Metabolic Networks and Pathways; Mice; Mice, Inbred C57BL; Middle Aged; Mutagenesis; Mutation; Nucleotides; Pancreas; Pancreatic Neoplasms; Protein Processing, Post-Translational; Proto-Oncogene Proteins p21(ras); Young Adult
Publisher
Cell Press
Type
journal article