Solute carrier transporters: the metabolic gatekeepers of immune cells.
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ABSTRACT:
SUBMITTER: Song W
PROVIDER: S-EPMC6977534 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:Solute Carrier (SLC) transporters are a large superfamily of transmembrane carriers involved in the regulated transport of metabolites, nutrients, ions and drugs across cellular membranes. A subset of these solute carriers play a significant role in the cellular uptake of many cancer therapeutics, ranging from chemotherapeutics such as antimetabolites, topoisomerase inhibitors, platinum-based drugs and taxanes to targeted therapies such as tyrosine kinase inhibitors. SLC transporters are co-expressed in groups and patterns across normal tissues, suggesting they may comprise a coordinated regulatory circuit serving to mediate normal tissue functions. In cancer however, there are dramatic changes in expression patterns of SLC transporters. This frequently serves to feed the increased metabolic demands of the tumor cell for amino acids, nucleotides and other metabolites, but also presents a therapeutic opportunity, as increased transporter expression may serve to increase intracellular concentrations of substrate drugs. In this review, we examine the regulation of drug transporters in cancer and how this impacts therapy response, and discuss novel approaches to targeting therapies to specific cancers via tumor-specific aberrations in transporter expression. We propose that among the oncogenic changes in SLC transporter expression there exist emergent vulnerabilities that can be exploited therapeutically, extending the application of precision medicine from tumor-specific drug targets to tumor-specific determinants of drug uptake.
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Project description:The solute carrier 6 (SLC6) family of the human genome comprises transporters for neurotransmitters, amino acids, osmolytes and energy metabolites. Members of this family play critical roles in neurotransmission, cellular and whole body homeostasis. Malfunction or altered expression of these transporters is associated with a variety of diseases. Pharmacological inhibition of the neurotransmitter transporters in this family is an important strategy in the management of neurological and psychiatric disorders. This review provides an overview of the biochemical and pharmacological properties of the SLC6 family transporters.
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Project description:Digestive system neoplasms are the leading causes of cancer-related death all over the world. Solute carrier (SLC) superfamily is composed of a series of transporters that are ubiquitously expressed in organs and tissues of digestive systems and mediate specific uptake of small molecule substrates in facilitative manner. Given the important role of SLC proteins in maintaining normal functions of digestive system, dysregulation of these protein in digestive system neoplasms may deliver biological and clinical significance that deserves systemic studies. In this review, we critically summarized the recent advances in understanding the role of SLC proteins in digestive system neoplasms. We highlighted that several SLC subfamilies, including metal ion transporters, transporters of glucose and other sugars, transporters of urea, neurotransmitters and biogenic amines, ammonium and choline, inorganic cation/anion transporters, transporters of nucleotide, amino acid and oligopeptide organic anion transporters, transporters of vitamins and cofactors and mitochondrial carrier, may play important roles in mediating the initiation, progression, metastasis, and chemoresistance of digestive system neoplasms. Proteins in these SLC subfamilies may also have diagnostic and prognostic values to particular cancer types. Differential expression of SLC proteins in tumors of digestive system was analyzed by extracting data from human cancer database, which revealed that the roles of SLC proteins may either be dependent on the substrates they transport or be tissue specific. In addition, small molecule modulators that pharmacologically regulate the functions of SLC proteins were discussed for their possible application in the treatment of digestive system neoplasms. This review highlighted the potential of SLC family proteins as drug target for the treatment of digestive system neoplasms.
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Project description:Acquisition of nutrients during intra-vacuolar growth of L. pneumophila within macrophages or amoebae is poorly understood. Since many genes of L. pneumophila are acquired by inter-kingdom horizontal gene transfer from eukaryotic hosts, we examined the presence of human solute carrier (SLC)-like transporters in the L. pneumophila genome using I-TASSER to assess structural alignments. We identified 11 SLC-like putative transporters in L. pneumophila that are structurally similar to SLCs, eight of which are amino acid transporters, and one is a tricarboxylate transporter. The two other transporters, LstA and LstB, are structurally similar to the human glucose transporter, SLC2a1/Glut1. Single mutants of lstA or lstB have decreased ability to import, while the lstA/lstB double mutant is severely defective for uptake of glucose. While lstA or lstB single mutants are not defective in intracellular proliferation within Acanthamoeba polyphaga and human monocyte-derived macrophages, the lstA/lstB double mutant is severely defective in both host cells. The two phenotypic defects of the lstA/lstB double mutant in uptake of glucose and intracellular replication are both restored upon complementation of either lstA or lstB. Our data show that the two glucose transporters, LstA and LstB, are redundant and are required for intracellular replication within human macrophages and amoebae.
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Project description:Hydroxyurea has proven laboratory and clinical therapeutic benefits for sickle cell anemia and other diseases, yet many questions remain about its in vivo pharmacokinetic and pharmacodynamic profiles. Previous reports suggest that hydroxyurea passively diffuses across cells, but its observed rapid absorption and distribution are more consistent with facilitated or active transport. We investigated the potential role of solute carrier (SLC) transporters in cellular uptake and accumulation of hydroxyurea.Passive diffusion of hydroxyurea across cell membranes was determined using the parallel artificial membrane permeability assay. SLC transporter screens were conducted using in vitro intracellular drug accumulation and transcellular transport assays in cell lines and oocytes overexpressing SLC transporters. Gene expression of SLC transporters was measured by real-time polymerase chain reaction in human tissues and cell lines.Hydroxyurea had minimal diffusion across a lipid bilayer but was a substrate for five different SLC transporters belonging to the organic cation/carnitine transporters and organic anion transporting polypeptides (OATP) families of transporters and urea transporters A and B. Further characterization of hydroxyurea transport revealed that cellular uptake by OATP1B3 is time- and temperature-dependent and inhibited by known substrates of OATP1B3. Urea transporters A and B are expressed differentially in human tissues and erythroid cells, and transport hydroxyurea bidirectionally via facilitated diffusion.These studies provide new insight into drug transport proteins that may be involved in the in vivo absorption, cellular distribution, and elimination of hydroxyurea. Elucidation of hydroxyurea transcellular movement should improve our understanding of its pharmacokinetics and pharmacodynamics, and may help explain some of the interpatient drug variability observed in patients with sickle cell anemia.
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Project description:Membrane transporter proteins play important roles in transport of nutrients into the cell, in transport of waste out of the cell, in maintenance of homeostasis, and in signal transduction. Solute carrier (SLC) transporter is the superfamily, which has the largest number of genes (>400 in humans) in membrane transporter and consists of 52 families. SLC transporters carry a wide variety of substrates such as amino acids, peptides, saccharides, ions, neurotransmitters, lipids, hormones and related materials. Despite the apparent importance for the substrate transport, the information of sequence variation and three-dimensional structures have not been integrated to the level of providing new knowledge on the relationship to, for instance, diseases. We, therefore, built a new database named iMusta4SLC, which is available at http://cib.cf.ocha.ac.jp/slc/, that connected the data of structural properties and of pathogenic mutations on human SLC transporters. iMusta4SLC helps to investigate the structural features of pathogenic mutations on SLC transporters. With this database, we found that the mutations at the conserved arginine were frequently involved in diseases, and were located at a border between the membrane and the cytoplasm. Especially in SLC families 2 and 22, the conserved residues formed a large cluster at the border. In SLC2A1, one third of the reported pathogenic missense mutations were found in this conserved cluster.
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Project description:Anticancer nucleoside analogs produce adverse, and at times, dose-limiting hematological toxicities that can compromise treatment efficacy, yet the mechanisms of such toxicities are poorly understood. Recently, cellular nucleoside transport has been implicated in normal blood cell formation with studies from nucleoside transporter-deficient mice providing additional insights into the regulation of mammalian hematopoiesis. Furthermore, several idiopathic human genetic disorders have revealed nucleoside transport as an important component of mammalian hematopoiesis because mutations in individual nucleoside transporter genes are linked to various hematological abnormalities, including anemia. Here, we review recent developments in nucleoside transporters, including their transport characteristics, their role in the regulation of hematopoiesis, and their potential involvement in the occurrence of adverse hematological side effects due to nucleoside drug treatment. Furthermore, we discuss the putative mechanisms by which aberrant nucleoside transport may contribute to hematological abnormalities and identify the knowledge gaps where future research may positively impact treatment outcomes for patients undergoing various nucleoside analog therapies.
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Project description:ObjectiveThe clinical use of paclitaxel is limited by variable responses and the potential for significant toxicity. To date, studies of associations between variants in candidate genes and paclitaxel effects have yielded conflicting results. We aimed to evaluate the relationships between global gene expression and paclitaxel sensitivity.MethodsWe utilized well-genotyped lymphoblastoid cell lines derived from the International HapMap Project to evaluate the relationships between cellular susceptibility to paclitaxel and global gene expression. Cells were exposed to varying concentrations of paclitaxel to evaluate paclitaxel-induced cytotoxicity and apoptosis. Among the top genes, we identified solute carrier (SLC) genes associated with paclitaxel sensitivity and narrowed down the list to those that had single nucleotide polymorphisms associated with both the expression level of the SLC gene and also with paclitaxel sensitivity. We performed an independent validation in an independent set of cell lines and also conducted functional studies using RNA interference.ResultsOf all genes associated with paclitaxel-induced cytotoxicity at P less than 0.05 (1713 genes), there was a significant enrichment in SLC genes (31 genes). A subset of SLC genes, namely SLC31A2, SLC43A1, SLC35A5, and SLC41A2, was associated with paclitaxel sensitivity and had regulating single nucleotide polymorphisms that were also associated with paclitaxel-induced cytotoxicity. Multivariate modeling demonstrated that those four SLC genes together explained 20% of the observed variability in paclitaxel susceptibility. Using RNA interference, we demonstrated increased paclitaxel susceptibility with knockdown of three SLC genes, SLC31A2, SLC35A5, and SLC41A2.ConclusionOur findings are novel and lend further support to the role of transporters, specifically solute carriers, in mediating cellular susceptibility to paclitaxel.
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Project description:The solute carrier (SLC) superfamily represents the biggest family of transporters with important roles in health and disease. Despite being attractive and druggable targets, the majority of SLCs remains understudied. One major hurdle in research on SLCs is the lack of tools, such as cell-based assays to investigate their biological role and for drug discovery. Another challenge is the disperse and anecdotal information on assay strategies that are suitable for SLCs. This review provides a comprehensive overview of state-of-the-art cellular assay technologies for SLC research and discusses relevant SLC characteristics enabling the choice of an optimal assay technology. The Innovative Medicines Initiative consortium RESOLUTE intends to accelerate research on SLCs by providing the scientific community with high-quality reagents, assay technologies and data sets, and to ultimately unlock SLCs for drug discovery.
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