Special Issue "ABC Transporters: From Basic Functions to Diseases"

A special issue of Cells (ISSN 2073-4409).

Deadline for manuscript submissions: 10 September 2019

Special Issue Editor

Guest Editor
Dr. Hiroshi Nakagawa

Department of Applied Biological Chemistry, College of Bioscience and Biotechnology, Chubu University, 1200 Matsumoto-cho, Kasugai, Aichi, 487-8501, Japan
Website | E-Mail
Interests: ABC transporters; drug resistance; metabolic diseases; natural products; SNPs

Special Issue Information

Dear Colleagues,

ATP-binding cassette (ABC) transporters constitute one of the largest superfamilies of integral membrane proteins, play crucial roles in the transport of various kinds of endogenous metabolites such as bile acids, sterols, lipids, and peptides, and exogenous molecules such as antibiotics, toxins, and drugs. A number of studies in this field have revealed that several of these transporters were mutated in human disorders such as Tangier disease, Stargardt disease and progressive familial intrahepatic cholestasis, as well as contributing to multi-drug resistances in cancer chemotherapy. In addition, evidence has recently accumulated showing that single nucleotide polymorphisms (SNPs) in the transporter genes determine the pharmacokinetics of various drugs and contribute to the development of various diseases. Thus, understanding of the clinical impacts of ABC transporters will provide us with potential targets for the prognosis and treatment of various diseases.

We invite authors to submit original research as well as review articles that will help in our understanding of the impacts of ABC transporters and their gene polymorphisms on human health, including the pathogenesis of multifactorial disorder such as metabolic diseases and the pharmacokinetics of drugs and multi-drug resistance in cancer chemotherapy. This Special Issue will improve our understanding of ABC transporters and also pave the way for alternative therapeutic strategies and the development of diagnostic and therapeutic approaches for some disease treatments.

Dr. Hiroshi Nakagawa
Guest Editor

Manuscript Submission Information

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Keywords

  • ATP-binding cassette (ABC) transporter
  • structure
  • function
  • drug resistance
  • genetic polymorphism
  • disease

Published Papers (3 papers)

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Research

Open AccessArticle
TNF-α Modulates P-Glycoprotein Expression and Contributes to Cellular Proliferation via Extracellular Vesicles
Received: 26 March 2019 / Revised: 21 May 2019 / Accepted: 23 May 2019 / Published: 24 May 2019
PDF Full-text (4266 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
P-glycoprotein (Pgp/ABCB1) overexpression is associated with multidrug resistance (MDR) phenotype and, consequently, failure in cancer chemotherapy. However, molecules involved in cell death deregulation may also support MDR. Tumor necrosis factor-alpha (TNF-α) is an important cytokine that may trigger either death or tumor growth. [...] Read more.
P-glycoprotein (Pgp/ABCB1) overexpression is associated with multidrug resistance (MDR) phenotype and, consequently, failure in cancer chemotherapy. However, molecules involved in cell death deregulation may also support MDR. Tumor necrosis factor-alpha (TNF-α) is an important cytokine that may trigger either death or tumor growth. Here, we examined the role of cancer cells in self-maintenance and promotion of cellular malignancy through the transport of Pgp and TNF-α molecules by extracellular vesicles (membrane microparticles (MP)). By using a classical MDR model in vitro, we identified a positive correlation between endogenous TNF-α and Pgp, which possibly favored a non-cytotoxic effect of recombinant TNF-α (rTNF-α). We also found a positive feedback involving rTNF-α incubation and TNF-α regulation. On the other hand, rTNF-α induced a reduction in Pgp expression levels and contributed to a reduced Pgp efflux function. Our results also showed that parental and MDR cells spontaneously released MP containing endogenous TNF-α and Pgp. However, these MP were unable to transfer their content to non-cancer recipient cells. Nevertheless, MP released from parental and MDR cells elevated the proliferation index of non-tumor cells. Collectively, our results suggest that Pgp and endogenous TNF-α positively regulate cancer cell malignancy and contribute to changes in normal cell behavior through MP. Full article
(This article belongs to the Special Issue ABC Transporters: From Basic Functions to Diseases)
Figures

Figure 1

Open AccessArticle
Functional Characterization of Clinically-Relevant Rare Variants in ABCG2 Identified in a Gout and Hyperuricemia Cohort
Received: 20 March 2019 / Revised: 15 April 2019 / Accepted: 15 April 2019 / Published: 18 April 2019
PDF Full-text (1891 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
ATP-binding cassette subfamily G member 2 (ABCG2) is a physiologically important urate transporter. Accumulating evidence demonstrates that congenital dysfunction of ABCG2 is an important genetic risk factor in gout and hyperuricemia; recent studies suggest the clinical significance of both common and rare variants [...] Read more.
ATP-binding cassette subfamily G member 2 (ABCG2) is a physiologically important urate transporter. Accumulating evidence demonstrates that congenital dysfunction of ABCG2 is an important genetic risk factor in gout and hyperuricemia; recent studies suggest the clinical significance of both common and rare variants of ABCG2. However, the effects of rare variants of ABCG2 on the risk of such diseases are not fully understood. Here, using a cohort of 250 Czech individuals of European descent (68 primary hyperuricemia patients and 182 primary gout patients), we examined exonic non-synonymous variants of ABCG2. Based on the results of direct sequencing and database information, we experimentally characterized nine rare variants of ABCG2: R147W (rs372192400), T153M (rs753759474), F373C (rs752626614), T421A (rs199854112), T434M (rs769734146), S476P (not annotated), S572R (rs200894058), D620N (rs34783571), and a three-base deletion K360del (rs750972998). Functional analyses of these rare variants revealed a deficiency in the plasma membrane localization of R147W and S572R, lower levels of cellular proteins of T153M and F373C, and null urate uptake function of T434M and S476P. Accordingly, we newly identified six rare variants of ABCG2 that showed lower or null function. Our findings contribute to deepening the understanding of ABCG2-related gout/hyperuricemia risk and the biochemical characteristics of the ABCG2 protein. Full article
(This article belongs to the Special Issue ABC Transporters: From Basic Functions to Diseases)
Figures

Figure 1

Open AccessArticle
A Human ABC Transporter ABCC4 Gene SNP (rs11568658, 559 G > T, G187W) Reduces ABCC4-Dependent Drug Resistance
Received: 26 November 2018 / Revised: 27 December 2018 / Accepted: 3 January 2019 / Published: 10 January 2019
PDF Full-text (1588 KB) | HTML Full-text | XML Full-text
Abstract
Broad-spectrum drug resistance is a major obstacle in cancer treatment, which is often caused by overexpression of ABC transporters the levels of which vary between individuals due to single-nucleotide polymorphisms (SNPs) in their genes. In the present study, we focused on the human [...] Read more.
Broad-spectrum drug resistance is a major obstacle in cancer treatment, which is often caused by overexpression of ABC transporters the levels of which vary between individuals due to single-nucleotide polymorphisms (SNPs) in their genes. In the present study, we focused on the human ABC transporter ABCC4 and one major non-synonymous SNP variant of the ABCC4 gene in the Japanese population (rs11568658, 559 G > T, G187W) whose allele frequency is 12.5%. Cells expressing ABCC4 (G187W) were established using the Flp-In™ system based on Flp recombinase-mediated transfection to quantitatively evaluate the impacts of this non-synonymous SNP on drug resistance profiles of the cells. Cells expressing ABCC4 (WT) or (G187W) showed comparable ABCC4 mRNA levels. 3-(4,5-Dimethyl-2-thiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay indicated that the EC50 value of the anticancer drug, SN-38, against cells expressing ABCC4 (G187W) was 1.84-fold lower than that against cells expressing ABCC4 (WT). Both azathioprine and 6-mercaptopurine showed comparable EC50 values against cells expressing ABCC4 (G187W) and those expressing ABCC4 (WT). These results indicate that the substitution of Gly at position 187 of ABCC4 to Trp resulted in reduced SN-38 resistance. Full article
(This article belongs to the Special Issue ABC Transporters: From Basic Functions to Diseases)
Figures

Graphical abstract

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

1. Type: Article
Tentative title: Untranslated regions in ABC genes
Authors: Pavel Dvorak and Pavel Soucek (Charles University in Prague)

Abstract: In eukaryotes, untranslated regions that bracket protein coding regions of genes play a pivotal role in gene expression regulation especially on the translation regulation level. Experimental as well as bioinformatics studies revealed different kinds of functionally relevant sequences localized within untranslated regions. Disruption of these hot spots by congenital as well as acquired mutations can lead to serious clinical consequences. Although untranslated regions were well studied in many genes, with important discoveries, the information regarding these regions within the ABC gene family is scarce and worth further exploration. Moreover, whole exon sequencing approaches often ignore untranslated regions and leave them out of their scope. We will focus on this topic in our proposed article.

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