Role of human nucleoside transporters in pancreatic cancer and chemoresistance

Abstract

The prognosis of pancreatic cancer is poor with the overall 5-year survival rate of less than 5% changing minimally over the past decades and future projections predicting it developing into the second leading cause of cancer related mortality within the next decade. Investigations into the mechanisms of pancreatic cancer development, progression and acquired chemoresistance have been constant for the past few decades, thus resulting in the identification of human nucleoside transporters and factors affecting cytotoxic uptake via said transporters. This review summaries the aberrant expression and role of human nucleoside transports in pancreatic cancer, more specifically human equilibrative nucleoside transporter 1/2 (hENT1, hENT2), and human concentrative nucleoside transporter 1/3 (hCNT1, hCNT3), while briefly discussing the connection and importance between these nucleoside transporters and mucins that have also been identified as being aberrantly expressed in pancreatic cancer. The review also discusses the incidence, current diagnostic techniques as well as the current therapeutic treatments for pancreatic cancer. Furthermore, we address the importance of chemoresistance in nucleoside analogue drugs, in particular, gemcitabine and we discuss prospective therapeutic treatments and strategies for overcoming acquired chemoresistance in pancreatic cancer by the enhancement of human nucleoside transporters as well as the potential targeting of mucins using a combination of mucolytic compounds with cytotoxic agents.

Keywords: Gemcitabine; Human concentrative nucleotide transporters; Human equilibrative nucleoside transporters; Human nucleoside transporters; Mucins; Pancreatic cancer.

Figure 1

Pancreatic cancer progression beginning with normal pancreatic ductal cells which express MUC1, MUC5AB, MUC6, MUC17, and MUC20. Pancreatic ductal cells progress to hyperplasia (PanIN21A/1B) with columnar cells, followed by dysplasia (PanIN2) with a loss of polarity, papillary and finally In-situ carcinoma (PanIN3) with a loss in cell polarity, papillary, budding off and mitosis. An increased expression of MUC1, MUC6, MUC16 and neoexpression of MUC3, MUC4, and MUC5AC can be seen in pancreatic intraepithelial neoplasia’s. Pancreatic ductal cells also progress into MCN which has an increased expression of MUC1 and the neoexpression of MUC2 and MUC5AC. Early Kras mutation as well as late SMAD4 and TP53 inactivation is seen in both PanIN and MCN. Finally pancreatic ductal cells can progress into IPMN which are mucin producing neoplasms that present with an increased expression of MUC1 and MUC6 as well as neoexpression of MUC2, MUC4 and MUC5AC. IPMN also presents with a Kras mutation and the inactivation of TP53 and P16/CDKN2A. IPMN and MCN further progress to adenocarcinoma where MUC1, and MUC6 expression is increased and MUC3, MUC4, MUC5AC, MUC5AB, MUC7, MUC13, MUC16 and MUC17 are neoexpressed[2-4,68]. IPMN: Intraductal papillary mucinous neoplasm; PanIN: Pancreatic intraepithelial neoplasia; MCN: Mucinous cystic neoplasm.

Figure 2

Schematic representation of Gemcitabine transport, metabolism, intracellular activation, and deactivation. Gemcitabine (dFdC) is transported into the cell by nucleoside transporters: human equilibrative nucleoside transporter (hENT) human concentrative nucleoside transporter (hCNT) and is then catalysed by deoxycytidine kinase (dCK), which results in gemcitabine monophosphate (dFdCMP). It is then phosphorylated by nucleotide monophosphate kinase (NMPK) to gemcitabine diphosphate (dFdCDP). Finally, it is phosphorylated into gemcitabine triphosphate (dFdCTP) by nucleoside-diphosphate kinase (NDPK). Once metabolism is completed, gemcitabine enters the DNA resulting in the inhibition of DNA repair and replication. Gemcitabine or its phosphorylated metabolites are finally exported into the extracellular matrix by multidrug resistance protein 5 (MRP5)[22,26,27,41,69]. RRM1: Ribonucleotide reductase; CDA: Cytidine deaminase; DCTD: Deoxycytidylate deaminase; NDP: Nucleotide diphosphate.