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. LyAudrey 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. Serkova, Aaron R. Sasson, Jason B. Fleming, Jennifer M. Oliveto, Costas A. Lyssiotis, Lewis C. Cantley, Lyudmyla Berim, Pankaj K. Singh

Research output: Contribution to journalArticle

122 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)71-87.e7
JournalCancer Cell
Volume32
Issue number1
DOIs
StatePublished - Jul 10 2017

Keywords

  • HIF-1α
  • MUC1
  • cancer metabolism
  • chemotherapy resistance
  • gemcitabine
  • mucin
  • non-oxidative pentose phosphate pathway
  • nucleotide synthesis
  • pancreatic cancer
  • pyrimidine biosynthesis

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Shukla, S. K., Purohit, V., Mehla, K., Gunda, V., Chaika, N. V., Vernucci, E., King, R. J., Abrego, J., Goode, G. D., Dasgupta, A., Illies, A. L., Gebregiworgis, T., Dai, B., Augustine, J. J., Murthy, D., Attri, K. S., Mashadova, O., Grandgenett, P. M., Powers, R., ... Singh, P. K. (2017). MUC1 and HIF-1alpha Signaling Crosstalk Induces Anabolic Glucose Metabolism to Impart Gemcitabine Resistance to Pancreatic Cancer. Cancer Cell, 32(1), 71-87.e7. https://doi.org/10.1016/j.ccell.2017.06.004