@article{3ecddc54211545bc93a048c2b2c46590,
title = "Cytosolic 5′-nucleotidase 1A is overexpressed in pancreatic cancer and mediates gemcitabine resistance by reducing intracellular gemcitabine metabolites",
abstract = "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 = "Chemotherapeutic resistance, Cytosolic 5′-nucleotidase 1A, Gemcitabine, Pancreatic cancer",
author = "Patzak, {Melanie S.} and Vijayalakshmi Kari and Shilpa Patil and Hamdan, {Feda H.} and Goetze, {Robert G.} and Marius Brunner and Jochen Gaedcke and Julia Kitz and Jodrell, {Duncan I.} and Richards, {Frances M.} and Christian Pilarsky and Robert Gruetzmann and Petra R{\"u}mmele and Thomas Kn{\"o}sel and Elisabeth Hessmann and Volker Ellenrieder and Johnsen, {Steven A.} and Albrecht Neesse",
note = "Funding Information: Dr. Richards reports grants from Cancer Research UK, other (funding construction of the building and facilities) from CK Hutchison Holdings Limited, during the conduct of the study; non-financial support from Astra Zeneca, outside the submitted work. Funding Information: This work was supported by the Deutsche Krebshilfe (Max Eder group) [ 110972 and 70113213 ] to A.N. and PiPAC Consortium [ 70112505 ] to S.A.J., J.G., E.H. and V.E; the German Academic Exchange Service (DAAD) to F.H.H.; the Deutsche Forschungsgemeinschaft (DFG) [ JO 815/3-2 ] to S.A.J.; and the Else-Kr{\"o}ner-Fresenius-Stiftung to R.G.G. Cancer Research UK (CRUK) supports the Jodrell Group (DIJ and FMR). LC-MS/MS analyses were performed in the PKB core at the CRUK Cambridge Institute. The CRUK Cambridge Institute (Li Ka Shing Centre) was generously funded by CK Hutchison Holdings Limited, the University of Cambridge, The Atlantic Philanthropies and a range of other donors. None of the funders were involved in study design, data collection, data analysis and interpretation, writing of the manuscript, and in the decision to submit the manuscript for publication. Funding Information: This work was supported by the Deutsche Krebshilfe (Max Eder group) [110972 and 70113213] to A.N. and PiPAC Consortium [70112505] to S.A.J., J.G., E.H. and V.E; the German Academic Exchange Service (DAAD) to F.H.H.; the Deutsche Forschungsgemeinschaft (DFG) [JO 815/3-2] to S.A.J.; and the Else-Kr?ner-Fresenius-Stiftung to R.G.G. Cancer Research UK (CRUK) supports the Jodrell Group (DIJ and FMR). LC-MS/MS analyses were performed in the PKB core at the CRUK Cambridge Institute. The CRUK Cambridge Institute (Li Ka Shing Centre) was generously funded by CK Hutchison Holdings Limited, the University of Cambridge, The Atlantic Philanthropies and a range of other donors. None of the funders were involved in study design, data collection, data analysis and interpretation, writing of the manuscript, and in the decision to submit the manuscript for publication. Publisher Copyright: {\textcopyright} 2019 The Authors",
year = "2019",
month = feb,
doi = "10.1016/j.ebiom.2019.01.037",
language = "English (US)",
volume = "40",
pages = "394--405",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",
}