Concentrative nucleoside transporter 1 (hCNT1) promotes phenotypic changes relevant to tumor biology in a translocation-independent manner.

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.

• Authors: S Pérez-Torras, A Vidal-Pla, P Cano-Soldado, I Huber-Ruano, A Mazo, M Pastor-Anglada
• Journal: Cell death & disease (Cell Death Dis) Vol. 4 Pg. e648 (May 30 2013) ISSN: 2041-4889 [Electronic] England
• PMID: 23722537 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Membrane Transport Proteins
• Nucleosides
• cif nucleoside transporter
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases

Topics

• Adenocarcinoma (metabolism, pathology)
• Adenoviridae (genetics)
• Biological Transport
• Cell Cycle
• Cell Death
• Cell Line, Tumor
• Cell Shape
• Cell Survival
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Gene Expression
• Genetic Vectors
• Humans
• MAP Kinase Signaling System
• Membrane Transport Proteins (physiology)
• Neoplasm Transplantation
• Nucleosides (metabolism)
• Pancreatic Neoplasms (metabolism, pathology)
• Phenotype
• Proto-Oncogene Proteins c-akt (metabolism)
• Tumor Burden