MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer Academic Article uri icon


MeSH Major

  • Deoxycytidine
  • Drug Resistance, Neoplasm
  • Glucose
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mucin-1
  • Pancreatic Neoplasms


  • Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of hypoxia inducible factor-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs.


publication date

  • July 10, 2017



  • Academic Article



  • eng

PubMed Central ID

  • PMC5533091

Digital Object Identifier (DOI)

  • 10.1016/j.ccell.2017.06.004

PubMed ID

  • 28697344

Additional Document Info

start page

  • 71

end page

  • 87.e7


  • 32


  • 1