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Enzyme
Compound
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Target Concepts:
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Query: UMLS:C0262471 (
ENT
)
5,307
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Nucleoside transporters (NTs) are involved in the cytotoxicity and transcriptomic response induced by nucleoside analogues. A relationship between the expression of nucleoside transporters and response to therapy has been demonstrated in solid tumours, although the pattern of such expression is highly variable. Thus, a question is whether the transporter expression pattern rather than specific NT proteins might better explain the ability of tumour cells to respond to nucleoside-derived drug therapy. In this study we used the breast cancer cell lines MCF7 and MCF7-
hCNT1
(stably transfected with
hCNT1
) to determine whether
hCNT1
expression can complement hENT1 functional loss in the cytotoxicity and transcriptomic response triggered by nucleoside analogues. Expression of
hCNT1
slightly increased cell sensitivity to 5'-deoxy-5-fluorouridine (5'-DFUR). Inhibition of the endogenous equilibrative activity blocked 5'-DFUR cytotoxicity in MCF7 cells, but not in MCF7-
hCNT1
cells. Moreover, under equilibrative transport inhibition conditions, induction of some transcriptional targets of 5'-DFUR was blocked in MCF7 cells, whereas
ENT
-inhibition had no effect on the transcriptional response to 5'-DFUR in MCF7-
hCNT1
cells. To confirm the role of
hCNT1
in 5'-DFUR treatment, a panel of nucleoside derivatives suitable for
hCNT1
-inhibition was obtained. The molecule T-Ala inhibited
hCNT1
-mediated transport. Furthermore, the cytotoxic action of 5'-DFUR and the transcriptional changes produced by this nucleoside analogue were partially inhibited by T-Ala in MCF7-
hCNT1
cells. These results show a link between NT function and the pharmacogenomic response to nucleoside analogues and further support the hypothesis that the expression pattern rather than specific transporters determines the cytotoxic effect of nucleoside derivatives.
...
PMID:Compensatory effects of the human nucleoside transporters on the response to nucleoside-derived drugs in breast cancer MCF7 cells. 1805 67
Humans possess three members of the cation-coupled
concentrative nucleoside transporter
CNT (SLC 28) family,
hCNT1
-3:
hCNT1
is selective for pyrimidine nucleosides but also transports adenosine, hCNT2 transports purine nucleosides and uridine, and hCNT3 transports both pyrimidine and purine nucleosides.
hCNT1
/2 transport nucleosides using the transmembrane Na
+
electrochemical gradient, while hCNT3 is both Na
+
- and H
+
-coupled. By producing recombinant hCNT3 in Xenopus laevis oocytes, we have used radiochemical high performance liquid chromatography (HPLC) analysis to investigate the metabolic fate of transported [
3
H] or [
14
C] pyrimidine and purine nucleosides once inside cells. With the exception of adenosine, transported nucleosides were generally subject to minimal intracellular metabolism. We also used radiochemical HPLC analysis to study the mechanism by which adenosine functions as a low K
m
, low V
max
permeant of
hCNT1
.
hCNT1
-producing oocytes were pre-loaded with [
3
H] uridine, after which efflux of accumulated radioactivity was measured in transport medium alone, or in the presence of extracellular non-radiolabelled adenosine or uridine.
hCNT1
-mediated [
3
H]-efflux was stimulated by extracellular uridine, but inhibited by extracellular adenosine, with >95% of the radioactivity exiting cells being unmetabolized uridine, consistent with a low transmembrane mobility of the
hCNT1
/adenosine complex. Humans also possess four members of the equilibrative nucleoside transporter
ENT
(SLC 29) family, hENT1-4. Of these, hENT1 and hENT2 transport both nucleosides and nucleobases into and out of cells, but their relative contributions to nucleoside and nucleobase homeostasis and, in particular, to adenosine signaling via purinoreceptors, are not known. We therefore used HPLC to determine plasma nucleoside and nucleobase concentrations in wild-type, mENT1-, mENT2- and mENT1/mENT2-knockout (KO) mice, and to compare the findings with knockout of mCNT3. Results demonstrated that ENT1 was more important than ENT2 or CNT3 in determining plasma adenosine concentrations, indicated modest roles of ENT1 in the homeostasis of other nucleosides, and suggested that none of the transporters is a major participant in handling of nucleobases.
...
PMID:HPLC reveals novel features of nucleoside and nucleobase homeostasis, nucleoside metabolism and nucleoside transport. 3212 30
