Impact of Solute Carrier Transporters in Glioma Pathology: A Comprehensive Review

Abstract

Solute carriers (SLCs) are essential for brain physiology and homeostasis due to their role in transporting necessary substances across cell membranes. There is an increasing need to further unravel their pathophysiological implications since they have been proposed to play a pivotal role in brain tumor development, progression, and the formation of the tumor microenvironment (TME) through the upregulation and downregulation of various amino acid transporters. Due to their implication in malignancy and tumor progression, SLCs are currently positioned at the center of novel pharmacological targeting strategies and drug development. In this review, we discuss the key structural and functional characteristics of the main SLC family members involved in glioma pathogenesis, along with their potential targeting options to provide new opportunities for CNS drug design and more effective glioma management.

Keywords: SLC; brain tumors; gliomas; solute carriers; therapy; transporters; tumor microenvironment.

Figure 1

SLC1A5 (ASCT2) is a neutral amino acid transporter that shifts GB cellular metabolism from glucose to glutamine pathways, favoring tumor progression. SLC2A1 (GLUT1) increases glucose uptake in tumor cells. SLC3A2 is upregulated in glioma cells and forms dimers with various transporter light chains, such as SLC7A5 (LAT1), acting as a chaperone to facilitate their localization to the plasma membrane. LAT1 functions as an antiporter facilitating the influx of leucine, phenylalanine, and tryptophan, enhancing the activity of mTOR kinase in favor of tumor proliferation. GB cells also convert tryptophan into L-Kyn to proliferate and evade immune surveillance. SLC7A11 is the functional subunit of system Xc- that also includes the SLC3A2 heavy chain and functions as a L-cystine/L-glutamate antiporter, regulating cystine uptake that is then used to produce cysteine, the rate-limiting precursor for the synthesis of glutathione and ferroptosis. SLC6A4 (SERT) is responsible for serotonin uptake into glioma cells. SLC8A2 (NCX2) is a Na⁺/Ca2⁺ exchanger (NCX2), regulating Ca2⁺-dependent cellular processes. It inhibits invasion and migration in GB cell lines, acting as a tumor suppressor. SLC9A1 (NHE-1) transports Na⁺ ions into the cell, also promoting ECM remodeling, cellular migration, and angiogenesis. SLC12A2 (NKCC1) is a Na-K-2Cl cotransporter-1, transporting Cl⁻ ions through the plasma membrane, with high-grade GB cells having significantly enhanced NKCC1 activity and thereby elevated Cl^- levels. SLC16A1 (MCT1) allows for the transport of protons and lactate and enhances tumor progression through cellular metabolic modifications. SLC17A7/VGLUT1, a glutamate transporter, acts as a bivalent tumor suppressor that inhibits GB proliferation, migration, and invasion. SLC18A2 is responsible for the transport of monoamine neurotransmitters and its abnormal expression may induce glioma proliferation. SLC22A5 (OCTN2) comprises the high-affinity carnitine transporter, with SLC22A5 being upregulated in glioma cells and different SLC22A5 expression levels being correlated with FAO rates and carnitine transport. SLC30A3 (ZnT-3) aids in the accumulation of zinc ions but appears to be significantly decreased in GB cell lines. SLC39A1 (ZIP1) actively transports zinc into cells and its expression is enhanced in glioma tissues, favoring tumor progression.