Cytosolic 5′-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolitesResearch in context
Melanie S. Patzak,
Vijayalakshmi Kari,
Shilpa Patil,
Feda H. Hamdan,
Robert G. Goetze,
Marius Brunner,
Jochen Gaedcke,
Julia Kitz,
Duncan I. Jodrell,
Frances M. Richards,
Christian Pilarsky,
Robert Gruetzmann,
Petra Rümmele,
Thomas Knösel,
Elisabeth Hessmann,
Volker Ellenrieder,
Steven A. Johnsen,
Albrecht Neesse
Affiliations
Melanie S. Patzak
University Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, Germany
Vijayalakshmi Kari
University Medical Center Goettingen, Department of General, Visceral and Pediatric Surgery, Goettingen, Germany
Shilpa Patil
University Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, Germany
Feda H. Hamdan
University Medical Center Goettingen, Department of General, Visceral and Pediatric Surgery, Goettingen, Germany
Robert G. Goetze
University Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, Germany
Marius Brunner
University Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, Germany
Jochen Gaedcke
University Medical Center Goettingen, Department of General, Visceral and Pediatric Surgery, Goettingen, Germany
Julia Kitz
University Medical Center Goettingen, Institute of Pathology, Goettingen, Germany
Duncan I. Jodrell
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
Frances M. Richards
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
Christian Pilarsky
University Medical Center Erlangen, Department of Surgery, Erlangen, Germany
Robert Gruetzmann
University Medical Center Erlangen, Department of Surgery, Erlangen, Germany
Petra Rümmele
University Medical Center Erlangen, Institute of Pathology, Erlangen, Germany
Thomas Knösel
Ludwig Maximilian University Munich, Institute of Pathology, Munich, Germany
Elisabeth Hessmann
University Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, Germany
Volker Ellenrieder
University Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, Germany
Steven A. Johnsen
University Medical Center Goettingen, Department of General, Visceral and Pediatric Surgery, Goettingen, Germany
Albrecht Neesse
University Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, Germany; Corresponding author at: Department of Gastroenterology and Gastrointestinal Oncology, University Medical Center Goettingen, Georg-August-University, Robert-Koch-Str. 40, 37075 Goettingen, Germany.
Background: Cytosolic 5′-nucleotidase 1A (NT5C1A) dephosphorylates non-cyclic nucleoside monophosphates to produce nucleosides and inorganic phosphates. Here, we investigate NT5C1A expression in pancreatic ductal adenocarcinoma (PDAC) and its impact on gemcitabine metabolism and therapeutic efficacy. Methods: NT5C1A expression was determined by semiquantitative immunohistochemistry using tissue microarrays. Gemcitabine metabolites and response were assessed in several human and murine PDAC cell lines using crystal violet assays, Western blot, viability assays, and liquid chromatography tandem mass-spectrometry (LC-MS/MS). Findings: NT5C1A was strongly expressed in tumor cells of a large subgroup of resected PDAC patients in two independent patient cohorts (44–56% score 2 and 8–26% score 3, n = 414). In contrast, NT5C1A was expressed at very low levels in the tumor stroma, and neither stromal nor tumoral expression was a prognostic marker for postoperative survival. In vitro, NT5C1A overexpression increased gemcitabine resistance by reducing apoptosis levels and significantly decreased intracellular amounts of cytotoxic dFdCTP in +NT5C1A tumor cells. Co-culture experiments with conditioned media from +NT5C1A PSCs improved gemcitabine efficacy in tumor cells. In vivo, therapeutic efficacy of gemcitabine was significantly decreased and serum levels of the inactive gemcitabine metabolite dFdU significantly increased in mice bearing NT5C1A overexpressing tumors. Interpretation: NT5C1A is robustly expressed in tumor cells of resected PDAC patients. Moreover, NT5C1A mediates gemcitabine resistance by decreasing the amount of intracellular dFdCTP, leading to reduced tumor cell apoptosis and larger pancreatic tumors in mice. Further studies should clarify the role of NT5C1A as novel predictor for gemcitabine treatment response in patients with PDAC. Keywords: Cytosolic 5′-nucleotidase 1A, Chemotherapeutic resistance, Gemcitabine, Pancreatic cancer
