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

doi:10.1016/j.ccell.2017.06.004

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

Cancer Cell. 2017 Jul 10;32(1):71-87.e7. doi: 10.1016/j.ccell.2017.06.004.

Authors

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

Affiliations

¹ Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA.
² Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
³ Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
⁴ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵ Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
⁶ Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁷ Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁸ Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁹ Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE 68198, USA.
¹⁰ Department of Molecular Biology and Biochemistry, University of Málaga and IBIMA, 29071 Málaga, Spain.
¹¹ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Biological Sciences, The University of Texas at Dallas, 800 West Campbell Road, Richardson, TX 75080, USA.
¹³ Department of Radiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
¹⁴ Division of Medical Oncology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
¹⁵ Department of Anesthesiology, University of Colorado Denver, Aurora, CO 80045, USA.
¹⁶ Department of Surgery, Health Sciences Center T18-065, Stony Brook Medicine, Stony Brook, NY 11794, USA.
¹⁷ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48103, USA.
¹⁸ Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198-5950, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: [email protected].

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.

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

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Carbon / metabolism
Deoxycytidine / analogs & derivatives*
Deoxycytidine / therapeutic use
Digoxin / pharmacology
Drug Resistance, Neoplasm*
Gemcitabine
Glucose / metabolism*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Mucin-1 / metabolism*
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Pentose Phosphate Pathway
Prognosis
Pyrimidines / biosynthesis
Signal Transduction

Substances

HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
MUC1 protein, human
Mucin-1
Pyrimidines
Deoxycytidine
Digoxin
Carbon
Glucose
pyrimidine
Gemcitabine

Abstract

Publication types

MeSH terms

Substances

Grants and funding