MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer
Surendra K. Shukla, Vinee Purohit, Kamiya Mehla, Venugopal Gunda, Nina V. Chaika, Enza Vernucci, Ryan J. King, Jaime Abrego, Gennifer D. Goode, Aneesha Dasgupta, Alysha L. Illies, Teklab Gebregiworgis, Bingbing Dai, Jithesh J. Augustine, Divya Murthy, Kuldeep S. Attri, Oksana Mashadova, Paul M. Grandgenett, Robert Powers, Quan P. Ly, Audrey J. Lazenby, Jean L. Grem, Fang Yu, José M. Matés, John M. Asara, Jung-whan Kim, Jordan H. Hankins, Colin Weekes, Michael A. Hollingsworth, Natalie J. Sarkova, Aaron R. Sasson, Jason B. Fleming, Jennifer M. Oliveto, Costas A. Lyssiotis, Lewis C. Cantley, Lyudmyla Berim, Pankaj K. Singh
Index: 10.1016/j.ccell.2017.06.004
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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-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α orde novopyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression ofTKTandCTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs.