SLC6A14 and SLC38A5 Drive the Glutaminolysis and Serine–Glycine–One-Carbon Pathways in Cancer

Abstract

The glutaminolysis and serine–glycine–one-carbon pathways represent metabolic reactions that are reprogramed and upregulated in cancer; these pathways are involved in supporting the growth and proliferation of cancer cells. Glutaminolysis participates in the production of lactate, an oncometabolite, and also in anabolic reactions leading to the synthesis of fatty acids and cholesterol. The serine–glycine–one-carbon pathway is involved in the synthesis of purines and pyrimidines and the control of the epigenetic signature (DNA methylation, histone methylation) in cancer cells. Methionine is obligatory for most of the methyl-transfer reactions in the form of S-adenosylmethionine; here, too, the serine–glycine–one-carbon pathway is necessary for the resynthesis of methionine following the methyl-transfer reaction. Glutamine, serine, glycine, and methionine are obligatory to fuel these metabolic pathways. The first three amino acids can be synthesized endogenously to some extent, but the need for these amino acids in cancer cells is so high that they also have to be acquired from extracellular sources. Methionine is an essential amino acid, thus making it necessary for cancer cells to acquire this amino acid solely from the extracellular milieu. Cancer cells upregulate specific amino acid transporters to meet this increased demand for these four amino acids. SLC6A14 and SLC38A5 are the two transporters that are upregulated in a variety of cancers to mediate the influx of glutamine, serine, glycine, and methionine into cancer cells. SLC6A14 is a Na+/Cl− -coupled transporter for multiple amino acids, including these four amino acids. In contrast, SLC38A5 is a Na+-coupled transporter with rather restricted specificity towards glutamine, serine, glycine, and methionine. Both transporters exhibit unique functional features that are ideal for the rapid proliferation of cancer cells. As such, these two amino acid transporters play a critical role in promoting the survival and growth of cancer cells and hence represent novel, hitherto largely unexplored, targets for cancer therapy.

A three-sodium-to-glycine stoichiometry shapes the structural relationships of ATB0,+ with GlyT2 and GlyT1 in the SLC6 family

“…In particular, the lack of ATB 0,+ impairs intestinal fluid secretion in the context of cystic fibrosis and is responsible of Meconium Ileus at birth ( Ahmadi et al, 2018 ; Ruin et al, 2020 ). Ganapthy’s group has demonstrated the implication of ATB 0,+ in cancers, as one of the four amino-acid transporters with SLC1A5 , SLC7A5 , SLC7A11 that are up-regulated in tumors for matching the increased demand in amino acids for cell growth, and more particularly for glutamine and glycine ( Bhutia et al, 2014 ; Coothankandaswamy et al, 2016 ; Sikder et al, 2017 ; Sniegowski et al, 2021 ).…”

Expression and function of SLC38A5, an amino acid-coupled Na+/H+ exchanger, in triple-negative breast cancer and its relevance to macropinocytosis

“…Therefore, we envisaged that there should be some other transporter(s) which is/are upregulated in TNBC to supply amino acids in support of various metabolic pathways that are reprogrammed in cancer. We thought that SLC38A5 is an excellent candidate for TNBC because of its unique functional features [14,19,20]. It transports glutamine, glycine, serine, and methionine, coupled to the transmembrane Na + gradient [19,20].…”

“…It transports glutamine, glycine, serine, and methionine, coupled to the transmembrane Na + gradient [19,20]. These amino acids are expected to maintain two important metabolic pathways that are accelerated in cancer, namely glutaminolysis associated with ATP production and lipid synthesis, and one-carbon metabolism associated with nucleotide synthesis and epigenetic control of gene expression [14]. The transporter is also coupled to H + efflux, meaning that when amino acids are transported into cells via SLC38A5, the process is accompanied with the removal of H + from the cells, thus leading to intracellular alkalinization [20].…”

“…The increased demand for amino acids in cancer cells is met by upregulation of selective amino acid transporters. The most studied transporters for their role in cancer include SLC1A5 (Alanine-Serine-Cysteine Transporter 2 or ASCT2) [5][6][7][8], SLC7A5 (system L Amino acid Transporter 1 or LAT1) [5][6][7][8][9], SLC7A11 (system xc transporter or xCT) [5,6,10,11], and SLC6A14 (Amino acid Transporter B 0,+ or ATB 0,+ ) [5][6][7][8][12][13][14]. The contribution of each of these transporters to tumor promotion is the provision of selective amino acids to cancer cells, which might impact on a multitude of downstream metabolic pathways and signaling cascades.…”

“…Stated differently, SLC38A5 is an amino acid-coupled Na + /H + exchanger. The rationale for the present study to evaluate the expression and function of SLC38A5 in breast cancer is the following: (i) SLC38A5 is a target for the oncogene c-Myc [21]; (ii) the substrate selectivity of SLC38A5 suggests a potentially a key role for this transporter in cancer-associated metabolic pathways such as glutaminolysis (glutamine) and one-carbon metabolism (serine, glycine, and methionine) [14]; (iii) the efflux of H + coupled to amino acid entry fulfills dual needs in cancer cells, namely supply of amino acids and removal of H + [19,20], and (iv) Na + /H + exchanger is known to promote macropinocytosis, a novel mechanism for cellular entry of nutrients from extracellular medium [22,23], suggesting a possibility that SLC38A5 as an amino acid-coupled Na + /H + exchanger might also promote macropinocytosis in cancer cells.…”