Impact of Solute Carrier Transporters in Glioma Pathology: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Filippos Anagnostakis
,
Michail Kokkorakis
,
Mariam Markouli
,
Christina Piperi

Solute carriers (SLCs) are the largest family of transmembrane transporters (consisting of 439 proteins without the pseudogenes), which are divided into 65 subfamilies (60 of which have been identified in the brain). They play a crucial role in exchanging different substances such as nutrients, ions, metabolites, as well as drugs through biological membranes. Most SLCs share the same protein structure consisting of 12 presumed transmembrane segments with molecular mass ranging between 50 to 100 kDa.

  • solute carriers
  • transporters
  • SLC
  • brain tumors
  • gliomas
  • tumor microenvironment

1. Biochemical Characteristics and Physiological Role of Main SLC Family Members

Accumulating research evidence has shown that several SLCs are involved in brain pathophysiology contributing to tumor development, and they are described in more detail in this section.

1.1. Cation/Anion Transport

1.1.1. SLC1A5

The SLC1A5 gene is found on chromosome 19q13.3; it contains eight exons and encodes for the SLC1A5 protein, also known as Alanine–Serine–Cysteine Transporter 2 (ASCT2). It functions as a Na+-dependent neutral amino acid transporter on the cell plasma membrane [1]. In particular, it is responsible for the transportation of valine, alanine, and methionine into the cell and the bidirectional transportation of asparagine, glutamate, serine, and threonine [2], with cysteine as a modulator [3]. The regulation of ASCT2 expression depends on the availability of substrates, especially glutamate, which is the preferred substrate [3], leading to an increase in its expression [4].

1.1.2. SLC7A11

The SLC7A11 gene is found on chromosome 4q28.3 and encodes for the SLC7A11 protein, which is the functional subunit of the system Xc- [5]. It comprises two subunits, namely, the light chain SLC7A11 (xCT) and the heavy chain SLC3A2 [5], with the latter anchoring the former to the plasma membrane, maintaining its stability [6]. This complex functions on the cell surface as a Na+-independent, CL−-dependent anionic L-cystine/L-glutamate antiporter and regulates the uptake of cystine found extracellularly, passing on glutamate located intracellularly at a 1:1 molar ratio [5]. Cystine from extracellular sources is transported inside the cell via SLC7A11, where it is used to produce cysteine after reduction in NADPH [6], the rate-limiting precursor for the synthesis of glutathione and ferroptosis. It has also been suggested to affect malignant cancer behavior, the TME, the function of the immune system, cancer-associated syndromes, as well as the sensitivity to therapy [5]. SLC7A11 expression can be modulated and tightly controlled in transcriptional, post-transcriptional, and post-translational levels as well as through epigenetic mechanisms [6].

1.1.3. SLC8A2

The solute carrier family 8-member 2 (SLC8A2) gene, also named the sodium/calcium exchanger 2 (NCX2), is located on chromosome 19q13.32 and consists of ten exons [7]. It is widely expressed in neuronal cells throughout the brain, however, without evidence of expression in other tissues [8]. The SLC8A2 gene encodes the Na+/Ca2+ exchangers (NCX2), which belong to the CaCA (Ca2+/Cation Antiporter) superfamily;therefore, SLC8A2 contributes to intracellular Ca2+ homeostasis [8]. Moreover, it enables the exchange of Ca2+ and Na+ ions through the cell membrane, regulating Ca2+-dependent cellular processes. Furthermore, it participates in the quick decrease in the cytoplasmic Ca2+ levels to baseline after neuronal activation, thereby modulating synaptic plasticity, learning, and memory processes. Lastly, SLC8A2 is involved in regulating the urinary excretion of Ca2+ and Na+ [9]. Studies indicate that changes in NCX2 expression in PC12 neuronal cells occur after activation of extracellular-signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs), with nerve growth factor (NGF) pharmacologically blocked or silenced [10].

1.1.4. SLC9A1

The sodium–hydrogen antiporter 1 (NHE-1), commonly referred to as SLC9A1, is encoded by the gene SLC9A1 in humans and is located on chromosome 1p36.11 and contains 17 exons. The NHE1 protein in humans consists of 815 amino acids, with a hydrophobic N-terminal membrane domain responsible for NHE transport, consisting of 500 amino acids, and a hydrophilic C-terminus located intracellularly, consisting of 315 amino acids. The mature NHE1 protein on the plasma membrane can be N- and O-glycosylated. However, glycosylation has not been associated with its function as a transporter [10][11]. The great majority of mammalian cells express NHE1. Quite often, NHE1 presents the “housekeeping” NHE isoform. NHE almost exclusively resides on the cellular surface, with the primary function to alkalize the cell by expelling H+ ions generated from metabolism or electrically driven acidification. Moreover, this antiporter presents the major pathway for the entry of Na+ ions into the cell, which along with Cl− and water uptake mediate the increase in regulatory volume following cell shrinkage. NHE1 additionally partakes in cell migration [12][13][14][15]. Lastly, the absence or loss of NHE1 in the brain membranes can modulate the activity of other transporters, which, in turn, leads to enhanced neuronal excitability [15].

1.1.5. SLC11A1

The SLC11A1 (solute carrier family 11 member 1 protein) was previously named NRAMP1 (natural resistance-associated macrophage protein 1) and is found in the human macrophage membrane. SLC11A1 is situated on chromosome 2q35, spans approximately 14 kilobases, and is comprised of 15 exons. SLC11A1 is only expressed among immune phagocytes recruited after phagocytosis to the phagosomal membrane and acts as a divalent cation transporter [16]. A microsatellite polymorphism at the SLC11A1 5’ terminal region that has a Z-DNA-forming dinucleotide repeat has been associated with the development of infections, autoimmunity, and diabetes in humans. During the activation of macrophages, membrane translocation to the late endosomes/lysosomes of the SLC11A1 protein takes place [17]. Its primary function is to act as an antiporter, facilitating the influx of cations into the phagolysosome or cytosol, according to the respective pH gradient [18]. Additionally, it impacts the formation of the inflammasome complex and influences the pro-inflammatory interleukins, IL-18 and IL-1β secreted from macrophages. It also regulates apoptosis by controlling the activity of cytosolic nucleotide-binding oligomerization domain proteins (NODs). Loss or gain of NOD protein functions may lead to a deregulated immune response [19]. It is also assumed that transcriptional activation of SLC11A1 may cause apoptotic events. On the other hand, transcriptional repression of SLC11A1 could have an impact on cell survival. It may also influence immune reactions against viral vector systems [20][21][22] by coordinating the processing of antigens and proteases’ catalytic activity in the late endosomes.

1.1.6. SLC12A2

The SLC12A2 gene is located on chromosome 1p13.2 and consists of six exons. SLC12A2 encodes for a protein known as NKCC1 (Na-K-2Cl cotransporter-1), which serves to transport and reabsorb sodium and chloride ions. In general, SLC12 family transporters mediate the transport of chloride ions along with sodium and/or potassium ions through epithelial and nonepithelial cell membranes [23]. It is largely known that With-No-Lysine (WNK) kinases can phosphorylate and activate oxidative stress response 1 (OSR1) and STE20/SPS1-related proline–alanine-rich protein kinase (SPAK) resulting in the ultimate phosphorylation and activation of NKCC1 that imports Na+, K+, and Cl− in the cell [23][24][25][26][27]. The dephosphorylation of NKCC1 is mainly carried out by protein phosphatase 1 (PP1) [28][29]. NKCC1 is expressed widely in the body and is localized at Cl− secreting epithelia [30], such as the salivary and sweat gland, intestine, and lung, where it mediates the electroneutral movement from the basal interstitium inside the cell of one K+, one Na+, and two Cl− ions.

1.1.7. SLC16A1

The SLC16A1 gene, also known as proton-coupled monocarboxylate transporter 1 (MCT1), located on chromosome 1p13.2, has six exons, and encodes for the ubiquitous protein MCT1 [31][32]. The expression of MCT1 can be enhanced by PPAR-α (Peroxisome proliferator-activated receptor alpha), Nrf2 (nuclear factor erythroid 2–related factor 2), and AMPK (AMP-activated protein kinase) [33]. MCT1 contains a binding site for substrates in the extracellular matrix, initially binding a proton and then a lactate anion. Consequently, this leads to a conformational change in the protein which allows the exposure of the proton and lactate to the opposite area from their release. The rate-limiting step for the net transport of lactic acid is MCT1′s return to an open conformation without a bound substrate, indicating a faster exchange of a monocarboxylate from the inside of the cell to the outside than its net transport across the membrane. Lastly, SLC16A1 has been shown to induce tumor progression through metabolic modifications in the cells [34][35][36][37]. Specifically, SLC16A1 is a target of Myc oncoproteins and its high levels present a characteristic feature of human cancers with MYC or MYCN involvement [38].

1.1.8. SLC30A3

The SLC30A3 gene is located at chromosome 2p23.3 and includes 12 exons. It encodes for Zinc transporter 3 (also known as solute carrier family 30 member 3, ZnT-3) and the membrane transport protein SLC30A. ZnT-3 is a protein found in synaptic vesicles enabling the accumulation of zinc ions [39][40]. Its function in zinc transport has also been associated with the modulation of memory formation via the extracellular signal-regulated kinases signaling pathway [41]. Furthermore, ZnT-3 and ZnT-10 downregulation in vascular smooth muscles has been involved in angiotensin-II-induced cell death [40].

1.1.9. SLC39A1

Zinc transporter ZIP1 constitutes a human protein, encoded by the SLC39A1 gene [42], which is located at chromosome 1q21.3 and consists of seven exons. The cardinal role of the protein ZIP1 is the active transportation of zinc into prostate cells.

1.2. Amino Acid Transport

1.2.1. SLC3A2

The SLC3A2 gene is found at chromosome 11q12.3, contains 13 exons, and encodes for the SLC3A2 protein, also called CD98 or 4F2 heavy chain (4F2hc). This is a 68 kDa type II glycoprotein [2] that has a single transmembrane domain, with its N-terminus in the cytoplasm and heavily glycosylated C-terminus on the cell surface. SLC3A2 forms dimers with various light chains of nutrient transporters such as SLC7A5 and this dimerization enables SLC3A2 to act as a chaperone, facilitating the localization of the transporters to the plasma membrane. The encoded transporter also plays a role in the regulation of intracellular calcium levels and transports L-type amino acids. The role of CD98 in development is crucial since its high expression is detected in the kidneys, placenta, testis, and bone marrow. The regulation of CD98 expression is dependent upon the ubiquitin ligases MARCH1 (membrane-associated RING-CH-type finger 1) and MARCH8, as well as pro-inflammatory cytokines, since there are many ubiquitination sites in SLC3A2 and SLC7A5, with CD98 being responsible for their trafficking [3].

1.2.2. SLC7A5

The SLC7A5 gene is found at chromosome 16q24.2, contains 10 exons [3], and encodes for a 55 kDa protein serving as a functional light chain, also called Large Amino Acid Transporter 1 (LAT1) [9]. LAT1 is part of the SLC7 family, which is a subset of the larger APC (amino acid–polyamine–Organo cation) superfamily [3] and functions as a Na+-independent antiporter. LAT1 exhibits a high affinity to large, branched chain, and aromatic amino acids, especially leucine, phenylalanine, and tryptophan. Additionally, it is capable of transporting both D- and L-amino acid enantiomers [43]. It forms a heterodimeric amino acid transporter [3], connected with a disulfide bridge to a 4F2 heavy chain (also called CD98). This heavy chain serves as a chaperone, aiding in the recruitment of the functional subunit to the cell membrane and stabilizing it [43], but without interfering with the transport activity of LAT1. LAT1 is involved in cell proliferation and development, especially in the bone marrow, brain, testis, and placenta, where it is highly expressed. However, due to its decreased expression in the intestine and limited capacity for transportation, LAT1 does not participate in amino acid absorption from the diet. Furthermore, the ability of LAT1 to facilitate the absorption of mercury compounds may be the reason for its fetal toxicity. The regulation of LAT1 expression depends on IL-2 secretion [3], the YAP1/TAZ pathway [44], miRNAs, lnc-RNAs, promoter methylation, and glucose levels [3].

1.2.3. SLC17A7

The SLC17A7 gene is located on chromosome 19q13.33 and consists of 11 exons [45]. It encodes for SLC17A7 (BNPI/ VGLUT1) [45], a metabolic vesicular Glutamate/H+ exchanger, located at the synaptic vesicles [46]. VGLUT1 is mainly involved in the transport of glutamate into the synaptic vesicles, maintaining the homeostasis of the glutamatergic system. It exerts its function by allowing H+ to flow into the synaptic vesicles by ATPase hydrolysis, thereby increasing membrane acidity that forms a pH gradient and a corresponding membrane potential change, providing the necessary power to transport glutamate [46]. VGLUT1 has a pivotal role in the CNS through the regulation of glutamine, especially in memory, learning, and synaptic plasticity [46].

1.2.4. SLC22A5

The SLC22A5 gene is located on chromosome 5q31.1 and consists of 11 exons. SLC22A5/OCTN2 comprises the unique, ubiquitously expressed, high-affinity carnitine plasma membrane transporter. Estrogens enable the regulation of the expression of SLC22A5 [47]. Moreover, proinflammatory cytokines, such as nuclear factor-κB (NF-κB) and tumor necrosis factor-α (TNF-α) stimulate SLC22A5 expression [48]. Additionally, there is an association between the increased phosphorylation of mTOR kinase and the activation of the transcription factor STAT3, which subsequently leads to an increase in the expression of SLC22A5 [49]. SLC22A5 comprises a plasma membrane protein that is co-translationally integrated into the membrane of the endoplasmic reticulum (ER). At the ER and at the initial extracellular loop of Golgi, SLC22A5 undergoes glycosylation [50] and is subsequently transported by vesicles to the cell surface, regulated by protein kinase C (PKC) [51].

1.3. Glucose Transport

SLC2A1

The SLC2A1 (GLUT1) gene is located on chromosome 1p34.2 and includes 10 exons. GLUT1 facilitates the minimal glucose uptake necessary to maintain cellular respiration. Reduced glucose levels amplify the expression of GLUT1 in cell membranes, while increased glucose levels decrease its expression [46]. There are various ways by which the GLUT1 (SLC2A1) expression is controlled at the transcriptional level. One such mechanism involves certain transcription factors, such as c-Myc (which is produced by the MYC oncogene) and sineoculis homeobox 1 (SIX1), which can directly activate the expression of GLUT1 as well as other glycolysis-related genes, thus leading to increased glycolysis [46]. Additionally, the expression of GLUT1 can be influenced by factors such as HIF-1α, insulin, thyroid hormone, and cancer suppressor genes [52]. The promotion of tumor angiogenesis and the upregulation of glucose metabolism genes are linked to HIF-1α. HIF-1α is activated under anaerobic conditions, binding to hypoxia response elements (HREs), which regulate the transcription of GLUT1-related genes. This causes the increased expression of GLUT1 and a higher glucose uptake in tumor cells. Hormonal regulation also has a significant impact on GLUT1 expression [52].

1.4. Neurotransmitter Transport

1.4.1. SLC6A2 (NET)

The SLC6A2 gene encodes for a multi-pass membrane protein, a member of the sodium/neurotransmitter symporter family. SLC6A2 is responsible for norepinephrine reuptake into presynaptic nerve terminals, thus regulating norepinephrine homeostasis [53].

1.4.2. SLC6A4 (SERT)

SERT is a member of the sodium/neurotransmitter symporter family and acts as an integral membrane protein that helps transport the neurotransmitter serotonin into presynaptic neurons from synaptic spaces in a sodium-dependent manner. This results in the termination of the action of serotonin and its recycling.

1.4.3. SLC18A2

The SLC18A2 gene encodes for a transmembrane protein that functions as a monoamine transporter of dopamine, serotonin, norepinephrine, and histamine. It mainly transports amine neurotransmitters into synaptic and secretory vesicles [54]. Polymorphisms of this gene have been associated with neurological and psychiatric diseases, including schizophrenia and bipolar disorder [54].

2. Therapeutic Targeting of SLCs

SLCs mediate the transport of a wide range of solutes in CNS, being involved in brain tumor pathology and participating actively in the uptake, metabolism, and excretion of drugs. Due to these properties, SLCs constitute promising drug targets and some family members have already been therapeutically exploited in gliomas (Table 1).
More specifically, the ER stress-inducing drug, 2-deoxy-D-glucose (2-DG), which targets tumor cells through GLUT1, appears to potentiate radiation responses in GB [55]. With respect to SLC3A2 involvement in gliomas, polyamine synthesis has been detected as enhanced in the pediatric type of diffuse intrinsic pontine gliomas (DIPG), thus increasing sensitivity to difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase 1 (ODC1), which is the rate-limiting step in polyamine synthesis. DIPG cells have been shown to upregulate the polyamine transporter SLC3A2, in order to compensate for ODC1 inhibition. Additionally, AMXT 1501, a polyamine transporter inhibitor was shown to reduce DIPG polyamine uptake and its combination with DFMO was further demonstrated to exert potent in vitro effects and extend survival in three DIPG orthotopic animal models. Therefore, these data suggest the promising effects of targeting polyamine uptake and synthesis as a potential therapeutic scheme for the devastating pediatric DIPGs and high-grade gliomas since the combination of AMXT 1501 and DFMO treatment effectively increased cell death and improved survival [56].
When it comes to NET, its therapeutic targeting is useful in advanced and refractory neuroblastoma, while NET-targeting 123I-metaiodobenzaguanidine (MIBG) therapy is an option for other neuroendocrine tumors as well [57].
Moreover, LAT1 was additionally demonstrated to affect drug uptake in GB cells. Novel chemotherapeutic approaches include the LAT1-mediated chemotherapy delivery and particularly WP1066-loaded liposomes with Amphi-DOPA administered intravenously, in combination with dendritic cell (DC)-targeted DNA vaccination. A DNA vaccine employing survivin, a known GB antigen, was used [57]. This combination significantly expanded the overall survival rate (by approximately 60%) of mice bearing orthotopic GB [58]. In another study, the uptake of nanoparticles loaded with doxorubicin and coupled with L-Phe by C6 glioma cells was achieved through the LAT1 transporter, ultimately leading to cancer cell cytotoxicity in an ex vivo setting [43]. Furthermore, the 3CDIT is a novel derivative of an amino acid that can cross the blood–brain barrier and target glioma tumor cells by interacting with the overexpressed LAT1 transporter [43].
Research studies have also shown that targeting the ribozyme-controlled HSVtk gene (human herpes simplex virus thymidine kinase type 1 gene) by overexpressing the miR-145 can lead to significant downregulation of various “metastasis-related genes”, including LAT1 [43]. On the other hand, treating medulloblastoma cells with the LAT1 inhibitor JPH203 over an extended period leads to cellular adaptation but not resistance, which ultimately impairs cell proliferation, survival, and migration [59]. JPH203 has the ability to inhibit the mTORC1 pathway, which can reduce the proliferation and survival of cancer cells, ultimately resulting in an effective and complete anticancer effect [43]. Finally, the phenylalanine derivative labeled with astatine, 211At-PA, targets system L amino acid transporters and was shown to suppress tumor proliferation in C6 and GL-261 glioma models. These derivatives have a short half-life and need to be distributed promptly to be effective in management, making them a potentially valuable option for non-responder patients with highly invasive glioma [60].
When it comes to radiotherapy, boron neutron capture therapy (BNCT) presents a treatment method utilizing boron irradiation with neutron beams to produce antineoplastic effects in cancer cells that are characterized by LAT1 overexpression [43]. BNCT allows for the application of high-dose particle radiation selectively to tumor cells in which boron phenylalanine is accumulated, such as glioma cells where accumulation increases with increasing tumor grade [61]. Combining BNCT with gene therapy is advantageous for treating tumors that have low expression of LAT1 [62]. The use of BSH-polyR has also been explored as a boron agent for BNCT in cells with low LAT1 expression and has been shown to effectively trigger BNCT-dependent apoptosis, particularly in CD44 high-expressing cells since the CD44 protein acts as a major target of BSH-polyR [63].
On the other hand, SLC8A2 is possibly a common regulator of endothelium-dependent and non-dependent U87MG cell angiogenesis, ultimately affecting glioma angiogenesis. Due to its combined endothelium-dependent and -independent inhibitory properties, SLC8A2 presents an emerging and promising target for anti-angiogenic therapy in the management of GB [7].
Moreover, a diuretic drug, bumetanide was shown to inhibit NKCC1 in GB, resulting in reduced migration of glioma cells in vitro, decreased invasion of peritumor tissue in vivo, and increased tumor cell apoptosis [64][65].
Finally, glioma cell survival has been shown to be heavily dependent on both fatty acid oxidation (FAO) and SLC22A5 activity because carnitine, which is required for FAO, is delivered to the cell by SLC22A5, which is upregulated in gliomas. Inhibition or overexpression of SLC22A5 in vitro was shown to reduce the survival of glioma cells through FAO modulation [66]. Additionally, a therapeutic approach targeting both SLC22A5 and carnitine palmitoylotransferase 1 (CPT1), which mediates the formation of acylcarnitine from L-carnitine required for FAO, was demonstrated to reduce glioma cell proliferation and provoke persistent apoptosis [66]. In agreement, the combination of a chemotherapeutic agent inhibiting carnitine uptake transported by SLC22A5, along with the CPT1 inhibitor etomoxir, exhibited a synergistic effect with a more robust inhibition of FAO, decreasing survival and enhancing glioma cell death [67].
Table 1. Main SLC family members involved in glioma pathogenesis with targeting potential.
SLC Carrier Type Role in Gliomas Therapeutic Targeting Clinical Trials References
SLC1A5 (ASCT2) Na+-dependent neutral amino acid transporter Shifts tumor cell metabolism from glucose to glutamine pathways     [1][68][69]
SLC2A1 (GLUT1) Glucose uptake transporter Increased expression in tumor cells that facilitates higher glucose uptake 2-DG potentiated the effects of radiation therapy in GB I
(NCT00096707)		 [52]
SLC3A2 Acts as a chaperone, facilitating the localization of the transporters to the plasma membrane Negatively correlates with CD8+ T cell levels; therefore, it is associated with decreased cancer cell killing
Transports essential amino acids and activates mTORC1, leading to tumor growth		 DFMO and AMXT 1501 co-administration in DIPG and high-grade glioma increased cell death and improved survival I/II
(NCT05500508)		 [69][70]
SLC6A2 (NET) Norepinephrine transporter   NET-targeting 123I-metaiodobenzaguanidine (MIBG) therapy   [57]
SLC6A4 (SERT) Monoamine serotonin transporter TNF-α increases SERT-dependent serotonin uptake into glioma cells and activates the MAPK signaling pathway     [71]
SLC7A5 (LAT1) Na+-independent antiporter, heterodimeric amino acid transporter Angiogenesis and cancer cell invasion
Facilitates amino acid influx and mTOR activity, aiding in tumor proliferation
Evasion of immune surveillance		 IV WP1066-loaded liposomes of Amphi-DOPA, combined with DC-targeted DNA vaccination in vivo
Nanoparticles loaded with doxorubicin and coupled with L-Phe
-3CDIT
-HSVtk gene targeting through miR-145 over-expression
-JPH203 LAT1 inhibitor
-211At-PA
-BNCT and BSH-polyR use		 I
(UMIN000016546)		 [3][44]
SLC7A11 Na+-independent,
Cl−-dependent anionic
L-cystine/L-glutamate antiporter		 Removes lipid peroxides and inhibits apoptosis, aiding in tumor proliferation
Immune cell regulation
Resistance to chemotherapy		     [5][6][72][73]
SLC8A2 (NCX2) Na+/Ca2+ exchanger Acts as a tumor suppressor, inhibiting tumor cell invasion
Negatively regulates angiogenesis		     [7][9]
SLC9A1 (NHE1) Na+-H+ antiporter-1 Promotes ECM remodeling and angiogenesis
Related to the accumulation of tumor-associated macrophages		     [10][12][13][14][74]
SLC11A1 (NRAMP1) Antiporter, facilitating the influx of cations into the phagolysosome or cytosol       [16][17]
SLC12A2 (NKCC1) Na-K-2Cl cotransporter-1 Linked to GB cell proliferation
Associated with aberrant and immature neuronal cells		 Bumetanide reduced GB migration and invasion   [23][27][65][75]
SLC16A1 (MCT1) Proton-coupled monocarboxylate transporter Increases glioma cell invasion and mitotic activity     [32][76]
SLC18A2 Monoamine/neurotransmitter transporter Promotes glioma formation     [77]
SLC22A5 (OCTN2) Carnitine plasma membrane transporter Correlated with FAO rates and carnitine transport
Associated with glioma cell viability and reduced apoptosis		 Combined SLC22A5 and CPT1 targeting
Chemotherapy inhibited carnitine uptake and etomoxir		   [47][66][67]
SLC30A3 Zinc transporter Inhibits GB cell growth and cell cycle progression
Inhibits EMT in GB
Represses GB malignant phenotype		     [78]
SLC39A1 Zinc transporter Promotes glioma cell proliferation
Influences immune cell infiltration in the glioma TME		     [42][79]

This entry is adapted from the peer-reviewed paper 10.3390/ijms24119393

References

  1. Scalise, M.; Pochini, L.; Console, L.; Losso, M.A.; Indiveri, C. The Human SLC1A5 (ASCT2) Amino Acid Transporter: From Function to Structure and Role in Cell Biology. Front. Cell Dev. Biol. 2018, 6, 96.
  2. Lopes, C.; Pereira, C.; Medeiros, R. ASCT2 and LAT1 Contribution to the Hallmarks of Cancer: From a Molecular Perspective to Clinical Translation. Cancers 2021, 13, 203.
  3. Scalise, M.; Galluccio, M.; Console, L.; Pochini, L.; Indiveri, C. The Human SLC7A5 (LAT1): The Intriguing Histidine/Large Neutral Amino Acid Transporter and Its Relevance to Human Health. Front. Chem. 2018, 6, 243.
  4. Teixeira, E.; Silva, C.; Martel, F. The Role of the Glutamine Transporter ASCT2 in Antineoplastic Therapy. Cancer Chemother. Pharmacol. 2021, 87, 447–464.
  5. Lin, W.; Wang, C.; Liu, G.; Bi, C.; Wang, X.; Zhou, Q.; Jin, H. SLC7A11/XCT in Cancer: Biological Functions and Therapeutic Implications. Am. J. Cancer Res. 2020, 10, 3106.
  6. Koppula, P.; Zhuang, L.; Gan, B. Cystine Transporter SLC7A11/XCT in Cancer: Ferroptosis, Nutrient Dependency, and Cancer Therapy. Protein Cell 2021, 12, 599–620.
  7. Qu, M.; Yu, J.; Liu, H.; Ren, Y.; Ma, C.; Bu, X.; Lan, Q. The Candidate Tumor Suppressor Gene SLC8A2 Inhibits Invasion, Angiogenesis and Growth of Glioblastoma. Mol. Cells 2017, 40, 761–772.
  8. Calabrese, L.; Serani, A.; Natale, S.; Tedeschi, V.; Guida, N.; Valsecchi, V.; Secondo, A.; Formisano, L.; Annunziato, L.; Molinaro, P. Identification and Characterization of the Promoter and Transcription Factors Regulating the Expression of Cerebral Sodium/Calcium Exchanger 2 (NCX2) Gene. Cell Calcium 2022, 102, 102542.
  9. SLC8A2—Sodium/Calcium Exchanger 2—Homo sapiens (Human)|UniProtKB|UniProt. Available online: https://www.uniprot.org/uniprotkb/Q9UPR5/entry (accessed on 27 March 2023).
  10. Counillon, L.; Pouysségur, J.; Reithmeier, R.A.F. The Na+/H+ Exchanger NHE-1 Possesses N- and O-Linked Glycosylation Restricted to the First N-Terminal Extracellular Domain. Biochemistry 1994, 33, 10463–10469.
  11. Haworth, R.S.; Frohlich, O.; Fliegel, L. Multiple Carbohydrate Moieties on the Na+/H+ Exchanger. Biochem. J. 1993, 289, 637–640.
  12. Denker, S.P.; Barber, D.L. Cell Migration Requires Both Ion Translocation and Cytoskeletal Anchoring by the Na-H Exchanger NHE1. J. Cell Biol. 2002, 159, 1087–1096.
  13. Denker, S.P.; Huang, D.C.; Orlowski, J.; Furthmayr, H.; Barber, D.L. Direct Binding of the Na–H Exchanger NHE1 to ERM Proteins Regulates the Cortical Cytoskeleton and Cell Shape Independently of H+ Translocation. Mol. Cell 2000, 6, 1425–1436.
  14. Schneider, L.; Stock, C.M.; Dieterich, P.; Jensen, B.H.; Pedersen, L.B.; Satir, P.; Schwab, A.; Christensen, S.T.; Pedersen, S.F. The Na+/H+ Exchanger NHE1 Is Required for Directional Migration Stimulated via PDGFR-Alpha in the Primary Cilium. J. Cell Biol. 2009, 185, 163–176.
  15. Xia, Y.; Zhao, P.; Xue, J.; Gu, X.Q.; Sun, X.; Yao, H.; Haddad, G.G. Na+ Channel Expression and Neuronal Function in the Na+/H+ Exchanger 1 Null Mutant Mouse. J. Neurophysiol. 2003, 89, 229–236.
  16. Cellier, M.F.M. Cell-Type Specific Determinants of NRAMP1 Expression in Professional Phagocytes. Biology 2013, 2, 233.
  17. Gruenheid, S.; Pinner, E.; Desjardins, M.; Gros, P. Natural Resistance to Infection with Intracellular Pathogens: The Nramp1 Protein Is Recruited to the Membrane of the Phagosome. J. Exp. Med. 1997, 185, 717–730.
  18. Goswami, T.; Bhattacharjee, A.; Babal, P.; Searle, S.; Moore, E.; Li, M.; Blackwell, J.M. Natural-Resistance-Associated Macrophage Protein 1 Is an H+/Bivalent Cation Antiporter. Biochem. J. 2001, 354, 511–519.
  19. Philpott, D.J.; Sorbara, M.T.; Robertson, S.J.; Croitoru, K.; Girardin, S.E. NOD Proteins: Regulators of Inflammation in Health and Disease. Nat. Rev. Immunol. 2014, 14, 9–23.
  20. Thorsen, F.; Afione, S.; Huszthy, P.C.; Tysnes, B.B.; Svendsen, A.; Bjerkvig, R.; Kotin, R.M.; Lønning, P.E.; Hoover, F. Adeno-Associated Virus (AAV) Serotypes 2, 4 and 5 Display Similar Transduction Profiles and Penetrate Solid Tumor Tissue in Models of Human Glioma. J. Gene Med. 2006, 8, 1131–1140.
  21. Xu, Y.F.; Zhang, Y.Q.; Xu, X.M.; Song, G.X. Papillomavirus Virus-like Particles as Vehicles for the Delivery of Epitopes or Genes. Arch. Virol. 2006, 151, 2133–2148.
  22. Zhang, X.; Godbey, W.T. Viral Vectors for Gene Delivery in Tissue Engineering. Adv. Drug Deliv. Rev. 2006, 58, 515–534.
  23. Koumangoye, R.; Bastarache, L.; Delpire, E. NKCC1: Newly Found as a Human Disease-Causing Ion Transporter. Function 2021, 2, zqaa028.
  24. Piechotta, K.; Lu, J.; Delpire, E. Cation Chloride Cotransporters Interact with the Stress-Related Kinases Ste20-Related Proline-Alanine-Rich Kinase (SPAK) and Oxidative Stress Response 1 (OSR1). J. Biol. Chem. 2002, 277, 50812–50819.
  25. Dowd, B.F.X.; Forbush, B. PASK (Proline-Alanine-Rich STE20-Related Kinase), a Regulatory Kinase of the Na-K-Cl Cotransporter (NKCC1). J. Biol. Chem. 2003, 278, 27347–27353.
  26. Gagnon, K.B.E.; England, R.; Delpire, E. Volume Sensitivity of Cation-Cl- Cotransporters Is Modulated by the Interaction of Two Kinases: Ste20-Related Proline-Alanine-Rich Kinase and WNK4. Am. J. Physiol. Cell Physiol. 2006, 290, C134–C142.
  27. Vitari, A.C.; Thastrup, J.; Rafiqi, F.H.; Deak, M.; Morrice, N.A.; Karlsson, H.K.R.; Alessi, D.R. Functional Interactions of the SPAK/OSR1 Kinases with Their Upstream Activator WNK1 and Downstream Substrate NKCC1. Biochem. J. 2006, 397, 223–231.
  28. Darman, R.B.; Flemmer, A.; Forbush, B. Modulation of Ion Transport by Direct Targeting of Protein Phosphatase Type 1 to the Na-K-Cl Cotransporter. J. Biol. Chem. 2001, 276, 34359–34362.
  29. Gagnon, K.B.; Delpire, E. Multiple Pathways for Protein Phosphatase 1 (PP1) Regulation of Na-K-2Cl Cotransporter (NKCC1) Function: The N-Terminal Tail of the Na-K-2Cl Cotransporter Serves as a Regulatory Scaffold for Ste20-Related Proline/Alanine-Rich Kinase (SPAK) AND PP1. J. Biol. Chem. 2010, 285, 14115–14121.
  30. Delpire, E.; Gagnon, K.B. Na+ -K+ -2Cl− Cotransporter (NKCC) Physiological Function in Nonpolarized Cells and Transporting Epithelia. Compr. Physiol. 2018, 8, 871–901.
  31. Garcia, C.K.; Goldstein, J.L.; Pathak, R.K.; Anderson, R.G.W.; Brown, M.S. Molecular Characterization of a Membrane Transporter for Lactate, Pyruvate, and Other Monocarboxylates: Implications for the Cori Cycle. Cell 1994, 76, 865–873.
  32. Garcia, C.K.; Li, X.; Luna, J.; Francke, U. CDNA Cloning of the Human Monocarboxylate Transporter 1 and Chromosomal Localization of the SLC16A1 Locus to 1p13.2-P12. Genomics 1994, 23, 500–503.
  33. Felmlee, M.A.; Jones, R.S.; Rodriguez-Cruz, V.; Follman, K.E.; Morris, M.E. Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease. Pharmacol. Rev. 2020, 72, 466–485.
  34. Berrios, C.; Padi, M.; Keibler, M.A.; Park, D.E.; Molla, V.; Cheng, J.; Lee, S.M.; Stephanopoulos, G.; Quackenbush, J.; DeCaprio, J.A. Merkel Cell Polyomavirus Small T Antigen Promotes Pro-Glycolytic Metabolic Perturbations Required for Transformation. PLoS Pathog. 2016, 12, e1006020.
  35. Le Floch, R.; Chiche, J.; Marchiq, I.; Naïken, T.; Ilk, K.; Murray, C.M.; Critchlow, S.E.; Roux, D.; Simon, M.P.; Pouysségur, J. CD147 Subunit of Lactate/H+ Symporters MCT1 and Hypoxia-Inducible MCT4 Is Critical for Energetics and Growth of Glycolytic Tumors. Proc. Natl. Acad. Sci. USA 2011, 108, 16663–16668.
  36. Payen, V.L.; Hsu, M.Y.; Rädecke, K.S.; Wyart, E.; Vazeille, T.; Bouzin, C.; Porporato, P.E.; Sonveaux, P. Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter. Cancer Res. 2017, 77, 5591–5601.
  37. Sprowl-Tanio, S.; Habowski, A.N.; Pate, K.T.; McQuade, M.M.; Wang, K.; Edwards, R.A.; Grun, F.; Lyou, Y.; Waterman, M.L. Lactate/Pyruvate Transporter MCT-1 Is a Direct Wnt Target That Confers Sensitivity to 3-Bromopyruvate in Colon Cancer. Cancer Metab. 2016, 4, 20.
  38. Doherty, J.R.; Yang, C.; Scott, K.E.N.; Cameron, M.D.; Fallahi, M.; Li, W.; Hall, M.A.; Amelio, A.L.; Mishra, J.K.; Li, F.; et al. Blocking Lactate Export by Inhibiting the Myc Target MCT1 Disables Glycolysis and Glutathione Synthesis. Cancer Res. 2014, 74, 908–920.
  39. Cole, T.B.; Wenzel, H.J.; Kafer, K.E.; Schwartzkroin, P.A.; Palmiter, R.D. Elimination of Zinc from Synaptic Vesicles in the Intact Mouse Brain by Disruption of the ZnT3 Gene. Proc. Natl. Acad. Sci. USA 1999, 96, 1716–1721.
  40. Patrushev, N.; Seidel-Rogol, B.; Salazar, G. Angiotensin II Requires Zinc and Downregulation of the Zinc Transporters ZnT3 and ZnT10 to Induce Senescence of Vascular Smooth Muscle Cells. PLoS ONE 2012, 7, e33211.
  41. Mott, D.D.; Dingledine, R. Unraveling the Role of Zinc in Memory. Proc. Natl. Acad. Sci. USA 2011, 108, 3103–3104.
  42. Yu, D.; Chen, Y.; Luo, M.; Peng, Y.; Yi, S. Upregulated Solute Carrier SLC39A1 Promotes Gastric Cancer Proliferation and Indicates Unfavorable Prognosis. Genet. Res. 2022, 2022, 1256021.
  43. Cappoli, N.; Jenkinson, M.D.; Dello Russo, C.; Dickens, D. LAT1, a Novel Pharmacological Target for the Treatment of Glioblastoma. Biochem. Pharmacol. 2022, 201, 115103.
  44. Onishi, Y.; Hiraiwa, M.; Kamada, H.; Iezaki, T.; Yamada, T.; Kaneda, K.; Hinoi, E. Hypoxia Affects Slc7a5 Expression through HIF-2α in Differentiated Neuronal Cells. FEBS openbio 2019, 9, 241–247.
  45. SLC17A7 Solute Carrier Family 17 Member 7 —Gene—NCBI. Available online: https://www.ncbi.nlm.nih.gov/gene/57030 (accessed on 8 April 2023).
  46. Du, X.; Li, J.; Li, M.; Yang, X.; Qi, Z.; Xu, B.; Liu, W.; Xu, Z.; Deng, Y. Research Progress on the Role of Type i Vesicular Glutamate Transporter (VGLUT1) in Nervous System Diseases. Cell Biosci. 2020, 10, 26.
  47. Wang, C.; Uray, I.P.; Mazumdar, A.; Mayer, J.A.; Brown, P.H. SLC22A5/OCTN2 Expression in Breast Cancer Is Induced by Estrogen via a Novel Intronic Estrogen-Response Element (ERE). Breast Cancer Res. Treat. 2012, 134, 101–115.
  48. Zhou, X.; Ringseis, R.; Wen, G.; Eder, K. The Pro-Inflammatory Cytokine Tumor Necrosis Factor α Stimulates Expression of the Carnitine Transporter OCTN2 (Novel Organic Cation Transporter 2) and Carnitine Uptake via Nuclear Factor-ΚB in Madin-Darby Bovine Kidney Cells. J. Dairy Sci. 2015, 98, 3840–3848.
  49. Ingoglia, F.; Visigalli, R.; Rotoli, B.M.; Barilli, A.; Riccardi, B.; Puccini, P.; Milioli, M.; Di Lascia, M.; Bernuzzi, G.; Dall’Asta, V. Human Macrophage Differentiation Induces OCTN2-Mediated L-Carnitine Transport through Stimulation of MTOR-STAT3 Axis. J. Leukoc. Biol. 2017, 101, 665–674.
  50. Di San Filippo, C.A.; Ardon, O.; Longo, N. Glycosylation of the OCTN2 Carnitine Transporter: Study of Natural Mutations Identified in Patients with Primary Carnitine Deficiency. Biochim. Biophys. Acta 2011, 1812, 312–320.
  51. Czeredys, M.; Samluk, Ł.; Michalec, K.; Tułodziecka, K.; Skowronek, K.; Nałȩcz, K.A. Caveolin-1—A Novel Interacting Partner of Organic Cation/Carnitine Transporter (Octn2): Effect of Protein Kinase C on This Interaction in Rat Astrocytes. PLoS ONE 2013, 8, e82105.
  52. Chen, C.; Pore, N.; Behrooz, A.; Ismail-Beigi, F.; Maity, A. Regulation of Glut1 MRNA by Hypoxia-Inducible Factor-1. Interaction between H-Ras and Hypoxia. J. Biol. Chem. 2001, 276, 9519–9525.
  53. SLC6A2 Solute Carrier Family 6 Member 2 —Gene—NCBI. Available online: https://www.ncbi.nlm.nih.gov/gene/6530#summary (accessed on 21 May 2023).
  54. SLC18A2 Solute Carrier Family 18 Member A2 —Gene—NCBI. Available online: https://www.ncbi.nlm.nih.gov/gene/6571 (accessed on 21 May 2023).
  55. Shah, S.S.; Rodriguez, G.A.; Musick, A.; Walters, W.M.; de Cordoba, N.; Barbarite, E.; Marlow, M.M.; Marples, B.; Prince, J.S.; Komotar, R.J.; et al. Targeting Glioblastoma Stem Cells with 2-Deoxy-D-Glucose (2-DG) Potentiates Radiation-Induced Unfolded Protein Response (UPR). Cancers 2019, 11, 159.
  56. Khan, A.; Gamble, L.D.; Upton, D.H.; Ung, C.; Yu, D.M.T.; Ehteda, A.; Pandher, R.; Mayoh, C.; Hébert, S.; Jabado, N.; et al. Dual Targeting of Polyamine Synthesis and Uptake in Diffuse Intrinsic Pontine Gliomas. Nat. Commun. 2021, 12, 971.
  57. Pandit-Taskar, N.; Modak, S. Norepinephrine Transporter as a Target for Imaging and Therapy. J. Nucl. Med. 2017, 58, 39S.
  58. Bhunia, S.; Vangala, V.; Bhattacharya, D.; Ravuri, H.G.; Kuncha, M.; Chakravarty, S.; Sistla, R.; Chaudhuri, A. Large Amino Acid Transporter 1 Selective Liposomes of l -DOPA Functionalized Amphiphile for Combating Glioblastoma. Mol. Pharm. 2017, 14, 3834–3847.
  59. Cormerais, Y.; Pagnuzzi-Boncompagni, M.; Schrötter, S.; Giuliano, S.; Tambutté, E.; Endou, H.; Wempe, M.F.; Pagès, G.; Pouysségur, J.; Picco, V. Inhibition of the Amino-Acid Transporter LAT1 Demonstrates Anti-Neoplastic Activity in Medulloblastoma. J. Cell Mol. Med. 2019, 23, 2711–2718.
  60. Watabe, T.; Kaneda-Nakashima, K.; Shirakami, Y.; Liu, Y.; Ooe, K.; Teramoto, T.; Toyoshima, A.; Shimosegawa, E.; Nakano, T.; Kanai, Y.; et al. Targeted Alpha Therapy Using Astatine (211At)-Labeled Phenylalanine: A Preclinical Study in Glioma Bearing Mice. Oncotarget 2020, 11, 1388–1398.
  61. Miyatake, S.I.; Kawabata, S.; Hiramatsu, R.; Kuroiwa, T.; Suzuki, M.; Kondo, N.; Ono, K. Boron Neutron Capture Therapy for Malignant Brain Tumors. Neurol. Med. Chir. 2016, 56, 361.
  62. Ohnishi, K.; Misawa, M.; Sikano, N.; Nakai, K.; Suzuki, M. Enhancement of Cancer Cell-Killing Effects of Boron Neutron Capture Therapy by Manipulating the Expression of L-Type Amino Acid Transporter 1. Radiat. Res. 2021, 196, 17–22.
  63. Fujimura, A.; Yasui, S.; Igawa, K.; Ueda, A.; Watanabe, K.; Hanafusa, T.; Ichikawa, Y.; Yoshihashi, S.; Tsuchida, K.; Kamiya, A.; et al. In Vitro Studies to Define the Cell-Surface and Intracellular Targets of Polyarginine-Conjugated Sodium Borocaptate as a Potential Delivery Agent for Boron Neutron Capture Therapy. Cells 2020, 9, 2149.
  64. Luo, L.; Wang, J.; Ding, D.; Hasan, M.N.; Yang, S.-S.; Lin, S.-H.; Schreppel, P.; Sun, B.; Yin, Y.; Erker, T.; et al. Role of NKCC1 Activity in Glioma K+ Homeostasis and Cell Growth: New Insights With the Bumetanide-Derivative STS66. Front. Physiol. 2020, 11, 911.
  65. Luo, L.; Guan, X.; Begum, G.; Ding, D.; Gayden, J.; Hasan, M.N.; Fiesler, V.M.; Dodelson, J.; Kohanbash, G.; Hu, B.; et al. Blockade of Cell Volume Regulatory Protein NKCC1 Increases TMZ-Induced Glioma Apoptosis and Reduces Astrogliosis. Mol. Cancer Ther. 2020, 19, 1550–1561.
  66. Juraszek, B.; Czarnecka-Herok, J.; Nałęcz, K.A. Glioma Cells Survival Depends Both on Fatty Acid Oxidation and on Functional Carnitine Transport by SLC22A5. J. Neurochem. 2021, 156, 642–657.
  67. Juraszek, B.; Nałąecz, K.A. SLC22A5 (OCTN2) Carnitine Transporter—Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer. Molecules 2020, 25, 14.
  68. Han, L.; Zhou, J.; Li, L.; Wu, X.; Shi, Y.; Cui, W.; Zhang, S.; Hu, Q.; Wang, J.; Bai, H.; et al. SLC1A5 Enhances Malignant Phenotypes through Modulating Ferroptosis Status and Immune Microenvironment in Glioma. Cell Death Dis. 2022, 13, 1071.
  69. Nachef, M.; Ali, A.K.; Almutairi, S.M.; Lee, S.H. Targeting SLC1A5 and SLC3A2/SLC7A5 as a Potential Strategy to Strengthen Anti-Tumor Immunity in the Tumor Microenvironment. Front. Immunol. 2021, 12, e624324.
  70. He, J.; Liu, D.; Liu, M.; Tang, R.; Zhang, D. Characterizing the Role of SLC3A2 in the Molecular Landscape and Immune Microenvironment across Human Tumors. Front. Mol. Biosci. 2022, 9, 961410.
  71. Malynn, S.; Campos-Torres, A.; Moynagh, P.; Haase, J. The Pro-Inflammatory Cytokine TNF-α Regulates the Activity and Expression of the Serotonin Transporter (SERT) in Astrocytes. Neurochem. Res. 2013, 38, 694–704.
  72. Koppula, P.; Zhang, Y.; Zhuang, L.; Gan, B. Amino Acid Transporter SLC7A11/ XCT at the Crossroads of Regulating Redox Homeostasis and Nutrient Dependency of Cancer. Cancer Commun. 2018, 38, 1–13.
  73. Jyotsana, N.; Ta, K.T.; DelGiorno, K.E. The Role of Cystine/Glutamate Antiporter SLC7A11/XCT in the Pathophysiology of Cancer. Front. Oncol. 2022, 12, 858462.
  74. Lagana, A.; Vadnais, J.; Le, P.U.; Nguyen, T.N.; Laprade, R.; Nabi, I.R.; Noel, J. Regulation of the Formation of Tumor Cell Pseudopodia by the Na(+)/H(+) Exchanger NHE1. J. Cell Sci. 2000, 113 Pt 20, 3649–3662.
  75. Garzon-Muvdi, T.; Schiapparelli, P.; ap Rhys, C.; Guerrero-Cazares, H.; Smith, C.; Kim, D.H.; Kone, L.; Farber, H.; Lee, D.Y.; An, S.S.; et al. Regulation of Brain Tumor Dispersal by NKCC1 through a Novel Role in Focal Adhesion Regulation. PLoS Biol. 2012, 10, e1001320.
  76. Lin, H.H.; Tsai, W.C.; Tsai, C.K.; Chen, S.H.; Huang, L.C.; Hueng, D.Y.; Hung, K.C. Overexpression of Cell-Surface Marker SLC16A1 Shortened Survival in Human High-Grade Gliomas. J. Mol. Neurosci. 2021, 71, 1614–1621.
  77. Kraboth, Z.; Kajtár, B.; Gálik, B.; Gyenesei, A.; Miseta, A.; Kalman, B. Involvement of the Catecholamine Pathway in Glioblastoma Development. Cells 2021, 10, 549.
  78. Zhang, L.; Liu, Z.; Dong, Y.; Kong, L. Epigenetic Targeting of SLC30A3 by HDAC1 Is Related to the Malignant Phenotype of Glioblastoma. IUBMB Life 2021, 73, 784–799.
  79. Wang, P.; Zhang, J.; He, S.; Xiao, B.; Peng, X. SLC39A1 Contribute to Malignant Progression and Have Clinical Prognostic Impact in Gliomas. Cancer Cell Int. 2020, 20, 573.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback