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


ABSTRACT: 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-1? (HIF-1?) mediates such metabolic reprogramming. Targeting HIF-1? 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.

SUBMITTER: Shukla SK 

PROVIDER: S-EPMC5533091 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Shukla Surendra K SK   Purohit Vinee V   Mehla Kamiya K   Gunda Venugopal V   Chaika Nina V NV   Vernucci Enza E   King Ryan J RJ   Abrego Jaime J   Goode Gennifer D GD   Dasgupta Aneesha A   Illies Alysha L AL   Gebregiworgis Teklab T   Dai Bingbing B   Augustine Jithesh J JJ   Murthy Divya D   Attri Kuldeep S KS   Mashadova Oksana O   Grandgenett Paul M PM   Powers Robert R   Ly Quan P QP   Lazenby Audrey J AJ   Grem Jean L JL   Yu Fang F   Matés José M JM   Asara John M JM   Kim Jung-Whan JW   Hankins Jordan H JH   Weekes Colin C   Hollingsworth Michael A MA   Serkova Natalie J NJ   Sasson Aaron R AR   Fleming Jason B JB   Oliveto Jennifer M JM   Lyssiotis Costas A CA   Cantley Lewis C LC   Berim Lyudmyla L   Singh Pankaj K PK  

Cancer cell 20170701 1


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 als  ...[more]

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