Cytosolic 5′-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolitesResearch in context
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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2019-02-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396419300416 |
| _version_ | 1830514963488178176 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Melanie S. Patzak |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-22T03:14:18Z |
| format | Article |
| id | doaj.art-195147ef850549bba1a4da0c7a0248e9 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-22T03:14:18Z |
| publishDate | 2019-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-195147ef850549bba1a4da0c7a0248e92022-12-21T18:40:52ZengElsevierEBioMedicine2352-39642019-02-0140394405Cytosolic 5′-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolitesResearch in contextMelanie S. Patzak0Vijayalakshmi Kari1Shilpa Patil2Feda H. Hamdan3Robert G. Goetze4Marius Brunner5Jochen Gaedcke6Julia Kitz7Duncan I. Jodrell8Frances M. Richards9Christian Pilarsky10Robert Gruetzmann11Petra Rümmele12Thomas Knösel13Elisabeth Hessmann14Volker Ellenrieder15Steven A. Johnsen16Albrecht Neesse17University Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, GermanyUniversity Medical Center Goettingen, Department of General, Visceral and Pediatric Surgery, Goettingen, GermanyUniversity Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, GermanyUniversity Medical Center Goettingen, Department of General, Visceral and Pediatric Surgery, Goettingen, GermanyUniversity Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, GermanyUniversity Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, GermanyUniversity Medical Center Goettingen, Department of General, Visceral and Pediatric Surgery, Goettingen, GermanyUniversity Medical Center Goettingen, Institute of Pathology, Goettingen, GermanyCancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United KingdomCancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United KingdomUniversity Medical Center Erlangen, Department of Surgery, Erlangen, GermanyUniversity Medical Center Erlangen, Department of Surgery, Erlangen, GermanyUniversity Medical Center Erlangen, Institute of Pathology, Erlangen, GermanyLudwig Maximilian University Munich, Institute of Pathology, Munich, GermanyUniversity Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, GermanyUniversity Medical Center Goettingen, Department of Gastroenterology and Gastrointestinal Oncology, Goettingen, GermanyUniversity Medical Center Goettingen, Department of General, Visceral and Pediatric Surgery, Goettingen, GermanyUniversity 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 cancerhttp://www.sciencedirect.com/science/article/pii/S2352396419300416 |
| spellingShingle | 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 Cytosolic 5′-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolitesResearch in context EBioMedicine |
| title | Cytosolic 5′-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolitesResearch in context |
| title_full | Cytosolic 5′-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolitesResearch in context |
| title_fullStr | Cytosolic 5′-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolitesResearch in context |
| title_full_unstemmed | Cytosolic 5′-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolitesResearch in context |
| title_short | Cytosolic 5′-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolitesResearch in context |
| title_sort | cytosolic 5 nucleotidase 1a is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolitesresearch in context |
| url | http://www.sciencedirect.com/science/article/pii/S2352396419300416 |
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