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Abstract
Nucleoside transporters (NTs) mediate the uptake of nucleosides and nucleobases across the plasma membrane, mostly for salvage purposes. The canonical NTs belong to two gene families, SLC29 and SLC28. The former encode equilibrative nucleoside transporter proteins (ENTs), which mediate the facilitative diffusion of natural nucleosides with broad selectivity, whereas the latter encode concentrative nucleoside transporters (CNTs), which are sodium-coupled and show high affinity for substrates with variable selectivity. These proteins are expressed in most cell types, exhibiting apparent functional redundancy. This might indicate that CNTs have specific roles in the physiology of the cell beyond nucleoside salvage. Here, we addressed this possibility using adenoviral vectors to restore tumor cell expression of hCNT1 or a polymorphic variant (hCNT1S546P) lacking nucleoside translocation ability. We found that hCNT1 restoration in pancreatic cancer cells significantly altered cell-cycle progression and phosphorylation status of key signal-transducing kinases, promoted poly-(ADP-ribose) polymerase hyperactivation and cell death and reduced cell migration. Importantly, the translocation-defective transporter triggered these same effects on cell physiology. Moreover, this study also shows that restoration of hCNT1 expression is able to reduce tumor growth in a mouse model of pancreatic adenocarcinoma. These data predict a novel role for a NT protein, hCNT1, which appears to be independent of its role as mediator of nucleoside uptake by cells. Thereby, hCNT1 fits the profile of a transceptor in a substrate translocation-independent manner and is likely to be relevant to tumor biology.
Highlights
Introductionconcentrative nucleoside transporters (CNT) differ in their substrate selectivity, whereas hCNT1 and hCNT2 accept only pyrimidine and purine nucleosides, respectively (with the exception of uridine, which is translocated by all SLC28 members), hCNT3 accepts both purines and pyrimidines as substrates.[1,2,3] CNT proteins, and hCNT1 in particular, are broadly detected in epithelia, their expression is often low to negligible in undifferentiated states, as reported for intestinal crypt cells, fetal hepatocytes and human tumors.[4,5,6,7,8] hCNT1 shows complex regulation by insulin in cardiac fibroblasts[9] and by hepatocyte nuclear factor (HNF)-4, bile acids,[10] tumor necrosis factor (TNF)-a and interleukin (IL)-611 in hepatocytes; its expression appears to be cell cycle dependent, showing upregulation at the S phase.[12] Most tumor-derived cell lines show low or even undetectable hCNT1 expression, their normal counterparts normally express this membrane protein
In order to examine its efficacy in inducing hCNT1-related function, we infected a panel of tumor cell lines with AdhCNT1 and the control adenovirus, Adctrol, at different multiplicities of infection (MOIs) and determined sodium-dependent cytidine uptake
This paper describes a novel and totally unexpected biological role for the Nucleoside transporters (NTs) protein hCNT1 that appears to be independent of its role as a mediator of nucleoside uptake by cells
Summary
CNTs differ in their substrate selectivity, whereas hCNT1 and hCNT2 accept only pyrimidine and purine nucleosides, respectively (with the exception of uridine, which is translocated by all SLC28 members), hCNT3 accepts both purines and pyrimidines as substrates.[1,2,3] CNT proteins, and hCNT1 in particular, are broadly detected in epithelia, their expression is often low to negligible in undifferentiated states, as reported for intestinal crypt cells, fetal hepatocytes and human tumors.[4,5,6,7,8] hCNT1 shows complex regulation by insulin in cardiac fibroblasts[9] and by hepatocyte nuclear factor (HNF)-4, bile acids,[10] tumor necrosis factor (TNF)-a and interleukin (IL)-611 in hepatocytes; its expression appears to be cell cycle dependent, showing upregulation at the S phase.[12] Most tumor-derived cell lines show low or even undetectable hCNT1 expression, their normal counterparts normally express this membrane protein Such is the case, for instance, for pancreatic adenocarcinoma and breast cancer.[6,7] ENTs may be considered. These studies revealed a biological function for hCNT1 that appears to be independent of its well-characterized nucleoside translocation role, providing the first evidence that a NT protein transduces signals to the cell interior and acts as a transceptor
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