Amino Acid Transporters as Targets for Cancer Therapy: Why, Where, When, and How

Abstract

Amino acids are indispensable for the growth of cancer cells. This includes essential amino acids, the carbon skeleton of which cannot be synthesized, and conditionally essential amino acids, for which the metabolic demands exceed the capacity to synthesize them. Moreover, amino acids are important signaling molecules regulating metabolic pathways, protein translation, autophagy, defense against reactive oxygen species, and many other functions. Blocking uptake of amino acids into cancer cells is therefore a viable strategy to reduce growth. A number of studies have used genome-wide silencing or knock-out approaches, which cover all known amino acid transporters in a large variety of cancer cell lines. In this review, these studies are interrogated together with other databases to identify vulnerabilities with regard to amino acid transport. Several themes emerge, such as synthetic lethality, reduced redundancy, and selective vulnerability, which can be exploited to stop cancer cell growth.

Keywords: ASCT2; GCN2; LAT1; SNAT1; SNAT2; mTOR; solute carrier; xCT.

Figure 1

Relationships between neutral and anionic amino acid transporters and metabolism. The main amino acid-related metabolic fluxes in cancer cells, such as glycolysis (pink), glutaminolysis (green), nucleobase biosynthesis (red), hexosamine pathway (blue), glutathione biosynthesis (orange), and pentose–phosphate pathway (brown), are shown. Amino acids are depicted in rounded frames. Transporters that feed into these pathways are depicted as blue spheres and their names are shown in italics. Adaptive changes caused by GCN2 activation are shown as double arrows. Reduced flux of carbon from pyruvate to acetyl-CoA is indicated by a dashed arrow. For more detailed depictions of transport mechanisms, see Figure 2.

Figure 2

Common amino acid transporters in cancer cells. Amino acid transporters, which are abundant in cancer cells, are shown. Antiporters (harmonizers) are shown in blue, uniporters and symporters in magenta (loaders), and lysosomal transporters in orange. Substrate specificity is indicated using AA⁰ (neutral amino acids) and AA⁺ (cationic amino acids, arginine, lysine, ornithine). Size of neutral amino acids is indicated as small (S, glycine, alanine, serine, cysteine, proline), medium (M, threonine, asparagine, glutamine), large (L, leucine, isoleucine, valine, methionine, phenylalanine, histidine, tryptophan, tyrosine). Links to signaling pathways are shown by dashed arrows.

Figure 3

Relationships between cationic amino acid transporters and metabolism. Arginine and ornithine metabolism in cancer cells. A full urea cycle is not expressed in cancer cells. Amino acids are depicted in rounded frames. Transporters that feed into these pathways are depicted as blue spheres and their names are shown in italics. For more detailed depictions of transport mechanism, see Figure 2. Abbreviations: ASS, arginine succinate synthetase; ASA, argininosuccinate; ASL, argininosuccinate lyase; ORC, ornithine carrier.