@article{2f853a1e1f0649698a5ceced92c9cac8,
title = "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-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. Shukla et al. identify that HIF-1α mediates increased glycolytic flux and de novo pyrimidine biosynthesis, leading to gemcitabine resistance in pancreatic cancer cells. Targeting HIF-1α or de novo pyrimidine biosynthesis increases the efficacy of gemcitabine.",
keywords = "HIF-1α, MUC1, cancer metabolism, chemotherapy resistance, gemcitabine, mucin, non-oxidative pentose phosphate pathway, nucleotide synthesis, pancreatic cancer, pyrimidine biosynthesis",
author = "Shukla, {Surendra K.} and Vinee Purohit and Kamiya Mehla and Venugopal Gunda and Chaika, {Nina V.} and Enza Vernucci and King, {Ryan J.} and Jaime Abrego and Goode, {Gennifer D.} and Aneesha Dasgupta and Illies, {Alysha L.} and Teklab Gebregiworgis and Bingbing Dai and Augustine, {Jithesh J.} and Divya Murthy and Attri, {Kuldeep S.} and Oksana Mashadova and Grandgenett, {Paul M.} and Robert Powers and Ly, {Quan P.} and Lazenby, {Audrey J.} and Grem, {Jean L.} and Fang Yu and Mat{\'e}s, {Jos{\'e} M.} and Asara, {John M.} and Kim, {Jung whan} and Hankins, {Jordan H.} and Colin Weekes and Hollingsworth, {Michael A.} and Serkova, {Natalie J.} and Sasson, {Aaron R.} and Fleming, {Jason B.} and Oliveto, {Jennifer M.} and Lyssiotis, {Costas A.} and Cantley, {Lewis C.} and Lyudmyla Berim and Singh, {Pankaj K.}",
note = "Funding Information: We would like to thank Dr. Prakash Radhakrishnan for technical assistance with initial animal studies. This work was supported in part by funding from the NIH grants ( R01 CA163649 , R01 CA210439 , and R01 CA216853 , NCI) to P.K.S. and ( P01CA117969 ) to L.C.C.; American Association for Cancer Research (AACR) – Pancreatic Cancer Action Network (PanCAN) Career Development Award (30-20-25-SING) to P.K.S.; the Specialized Programs for Research Excellence (SPORE, 2P50 CA127297 , NCI) to P.K.S., J.L.G., and M.A.H.; Pancreatic Tumor Microenvironment Research Network (U54, CA163120 , NCI) to P.K.S. and M.A.H.; and Lustgarten Foundation award to L.C.C. J.M.M. thanks SAF2015-64501-R. We would also like to acknowledge the Fred & Pamela Buffett Cancer Center Support Grant ( P30CA036727 , NCI) and NCCS COBRE ( P30 GM106397 , NIGMS) for supporting shared resources and the Animal Imaging Shared Resources of the University of Colorado Cancer Center ( P30CA046934 , NCI). Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2017",
month = jul,
day = "10",
doi = "10.1016/j.ccell.2017.06.004",
language = "English (US)",
volume = "32",
pages = "71--87.e7",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "1",
}