MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer.

Authors:
Surendra K Shukla
Surendra K Shukla
The Eppley Institute for Research in Cancer and Allied Diseases
Vinee Purohit
Vinee Purohit
University of Nebraska Medical Center
United States
Kamiya Mehla
Kamiya Mehla
University of Nebraska Medical Center
United States
Venugopal Gunda
Venugopal Gunda
Boys Town National Research Hospital
United States
Nina V Chaika
Nina V Chaika
University of Nebraska Medical Center
United States
Enza Vernucci
Enza Vernucci
The Eppley Institute for Research in Cancer and Allied Diseases
Ryan J King
Ryan J King
The Eppley Institute for Research in Cancer and Allied Diseases
Omaha | United States
Jaime Abrego
Jaime Abrego
The Eppley Institute for Research in Cancer and Allied Diseases

Cancer Cell 2017 07;32(1):71-87.e7

Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address:

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.

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http://dx.doi.org/10.1016/j.ccell.2017.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533091PMC
July 2017
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