| Literature DB >> 28697344 |
Surendra K Shukla1, Vinee Purohit2, Kamiya Mehla1, Venugopal Gunda1, Nina V Chaika1, Enza Vernucci1, Ryan J King1, Jaime Abrego1, Gennifer D Goode1, Aneesha Dasgupta1, Alysha L Illies1, Teklab Gebregiworgis3, Bingbing Dai4, Jithesh J Augustine4, Divya Murthy1, Kuldeep S Attri1, Oksana Mashadova5, Paul M Grandgenett1, Robert Powers3, Quan P Ly6, Audrey J Lazenby7, Jean L Grem8, Fang Yu9, José M Matés10, John M Asara11, Jung-Whan Kim12, Jordan H Hankins13, Colin Weekes14, Michael A Hollingsworth1, Natalie J Serkova15, Aaron R Sasson16, Jason B Fleming4, Jennifer M Oliveto13, Costas A Lyssiotis17, Lewis C Cantley5, Lyudmyla Berim8, Pankaj K Singh18.
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.Entities:
Keywords: HIF-1α; MUC1; cancer metabolism; chemotherapy resistance; gemcitabine; mucin; non-oxidative pentose phosphate pathway; nucleotide synthesis; pancreatic cancer; pyrimidine biosynthesis
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Year: 2017 PMID： 28697344 PMCID： PMC5533091 DOI： 10.1016/j.ccell.2017.06.004
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 38.585