Role of drug-dependent transporter modulation on the chemosensitivity of cholangiocarcinoma

Urtasun, Nerea; Boces-Pascual, Clara; Boix, Loreto; Bruix, Jordi; Pastor‐Anglada, Marçal; Pérez-Torras, Sandra

doi:10.18632/oncotarget.21624

Cited by 6 publications

(5 citation statements)

References 45 publications

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“…Considering NTs have a major role in determining the bioavailability of several anticancer drugs, various studies have been performed to analyze their expression in cancer. In particular, it has been shown that hCNT1 expression is highly reduced or even lost in different types of tumors ( Farré et al, 2004 ; Gloeckner-Hofmann et al, 2006 ; Lane et al, 2010 ; Bhutia et al, 2011 ; Urtasun et al, 2017 ). Accordingly, hCNT1 biological function (hCNT1-related transport activity) is almost undetectable or null and its expression at the protein and mRNA level is often lost or dramatically reduced in cancer derived cell lines.…”

Section: Nts Beyond Transportmentioning

confidence: 99%

Emerging Roles of Nucleoside Transporters

2018

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Since human Nucleoside Transporters (hNTs) were identified by their activity as transport systems, extensive work has been done to fully characterize them at the molecular and physiological level. Many efforts have been addressed to the identification of their selectivity for natural substrates and nucleoside analogs used to treat several diseases. hNTs belong to two different gene families, SLC28 and SLC29, encoding human Concentrative Nucleoside Transporters (hCNTs) and human Equilibrative Nucleoside Transporters (hENTs), respectively. hCNTs and hENTs are integral membrane proteins, albeit structurally unrelated. Both families share common features as substrate selectivity and often tissue localization. This apparent biological redundancy may anticipate some different roles for hCNTs and hENTs in cell physiology. Thus, hENTs may have a major role in maintaining nucleoside homeostasis, whereas hCNTs could contribute to nucleoside sensing and signal transduction. In this sense, the ascription of hCNT1 to a transceptor reinforces this hypothesis. Moreover, some evidences could suggest a putative role of hCNT2 and hCNT3 as transceptors. The interacting proteins identified for hCNT2 suggest a link to energy metabolism. Moreover, the ability of hCNT2 and hCNT3 to transport adenosine links both proteins to purinergic signaling. On the other hand, the broad selectivity transporters hENTs have a crucial role in salvage pathways and purinergic signaling by means of nucleoside pools regulation. In particular, the two new hENT2 isoforms recently described together with hENT2 seem to be key elements controlling nucleoside and nucleotide pools for DNA synthesis. This review focuses on all these NTs functions beyond their mere translocation ability.

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Section: Nts Beyond Transportmentioning

confidence: 99%

Emerging Roles of Nucleoside Transporters

2018

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“…However, the actual situation appears to be more complex and, at least for hCNT1, even opposite that of expectations. Indeed, expression analyses have shown downregulation of hCNT1 at the mRNA level in HCC, PDAC, and cholangiocarcinoma tumors [15,[17][18][19]33]. However, these analyses, performed using homogenized samples that included the multiple cell types present in tumors-and even normal tissues-could underestimate hCNT1 levels.…”

Section: Discussionmentioning

confidence: 99%

OncomiRs miR-106a and miR-17 negatively regulate the nucleoside-derived drug transporter hCNT1

Boces-Pascual

Mata-Ventosa

Martı́n-Satué

et al. 2021

Cell. Mol. Life Sci.

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High-affinity uptake of natural nucleosides as well as nucleoside derivatives used in anticancer therapies is mediated by human concentrative nucleoside transporters (hCNTs). hCNT1, the hCNT family member that specifically transports pyrimidines, is also a transceptor involved in tumor progression. In particular, oncogenesis appears to be associated with hCNT1 downregulation in some cancers, although the underlying mechanisms are largely unknown. Here, we sought to address changes in colorectal and pancreatic ductal adenocarcinoma—both of which are important digestive cancers—in the context of treatment with fluoropyrimidine derivatives. An analysis of cancer samples and matching non-tumoral adjacent tissues revealed downregulation of hCNT1 protein in both types of tumor. Further exploration of the putative regulation of hCNT1 by microRNAs (miRNAs), which are highly deregulated in these cancers, revealed a direct relationship between the oncomiRs miR-106a and miR-17 and the loss of hCNT1. Collectively, our findings provide the first demonstration that hCNT1 inhibition by these oncomiRs could contribute to chemoresistance to fluoropyrimidine-based treatments in colorectal and pancreatic cancer. Graphic abstract

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“…CNT1 protein expression is lost in many of the epithelial tumors analyzed so far [ 84 , 85 , 86 ]. Restitution of CNT1 protein expression in pancreatic adenocarcinoma cell lines resulted in cell cycle arrest, non-apoptotic cell death, the inhibition of cell migration, and PARP hyperactivation, among other effects [ 87 ].…”

Section: Nucleoside and Nucleobase Transporter Protein Variants And D...mentioning

confidence: 99%

Inborn Errors of Nucleoside Transporter (NT)-Encoding Genes (SLC28 and SLC29)

Pastor‐Anglada

Mata-Ventosa

Pérez-Torras

2022

IJMS

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The proper regulation of nucleotide pools is essential for all types of cellular functions and depends on de novo nucleotide biosynthesis, salvage, and degradation pathways. Despite the apparent essentiality of these processes, a significant number of rare diseases associated with mutations in genes encoding various enzymes of these pathways have been already identified, and others are likely yet to come. However, knowledge on genetic alterations impacting on nucleoside and nucleobase transporters is still limited. At this moment three gene-encoding nucleoside and nucleobase transporter proteins have been reported to be mutated in humans, SLC29A1, SLC29A3, and SLC28A1, impacting on the expression and function of ENT1, ENT3, and CNT1, respectively. ENT1 alterations determine Augustine-null blood type and cause ectopic calcification during aging. ENT3 deficiency translates into various clinical manifestations and syndromes, altogether listed in the OMIM catalog as histiocytosis-lymphoadenopathy plus syndrome (OMIM#602782). CNT1 deficiency causes uridine-cytidineuria (URCTU) (OMIM#618477), a unique type of pyrimidineuria with an as yet not well-known clinical impact. Increasing knowledge on the physiological, molecular and structural features of these transporter proteins is helping us to better understand the biological basis behind the biochemical and clinical manifestations caused by these deficiencies. Moreover, they also support the view that some metabolic compensation might occur in these disturbances, because they do not seem to significantly impact nucleotide homeostasis, but rather other biological events associated with particular subtypes of transporter proteins.

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Role of drug-dependent transporter modulation on the chemosensitivity of cholangiocarcinoma

Cited by 6 publications

References 45 publications

Emerging Roles of Nucleoside Transporters

Emerging Roles of Nucleoside Transporters

OncomiRs miR-106a and miR-17 negatively regulate the nucleoside-derived drug transporter hCNT1

Inborn Errors of Nucleoside Transporter (NT)-Encoding Genes (SLC28 and SLC29)

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