Amino acid transporters within the solute carrier superfamily: Underappreciated proteins and novel opportunities for cancer therapy

Abstract

Background: Solute carrier (SLC) transporters, a diverse family of membrane proteins, are instrumental in orchestrating the intake and efflux of nutrients including amino acids, vitamins, ions, nutrients, etc, across cell membranes. This dynamic process is critical for sustaining the metabolic demands of cancer cells, promoting their survival, proliferation, and adaptation to the tumor microenvironment (TME). Amino acids are fundamental building blocks of cells and play essential roles in protein synthesis, nutrient sensing, and oncogenic signaling pathways. As key transporters of amino acids, SLCs have emerged as crucial players in maintaining cellular amino acid homeostasis, and their dysregulation is implicated in various cancer types. Thus, understanding the intricate connections between amino acids, SLCs, and cancer is pivotal for unraveling novel therapeutic targets and strategies.

Scope of review: In this review, we delve into the significant impact of amino acid carriers of the SLCs family on the growth and progression of cancer and explore the current state of knowledge in this field, shedding light on the molecular mechanisms that underlie these relationships and highlighting potential avenues for future research and clinical interventions.

Major conclusions: Amino acids transportation by SLCs plays a critical role in tumor progression. However, some studies revealed the tumor suppressor function of SLCs. Although several studies evaluated the function of SLC7A11 and SLC1A5, the role of some SLC proteins in cancer is not studied well. To exert their functions, SLCs mediate metabolic rewiring, regulate the maintenance of redox balance, affect main oncogenic pathways, regulate amino acids bioavailability within the TME, and alter the sensitivity of cancer cells to therapeutics. However, different therapeutic methods that prevent the function of SLCs were able to inhibit tumor progression. This comprehensive review provides insights into a rapidly evolving area of cancer biology by focusing on amino acids and their transporters within the SLC superfamily.

Keywords: Amino acid; Cancer; Cancer metabolism; Nutrient sensing; SLC.

Graphical abstract

Figure 1

SLCs and the systems by which they transport amino acids. These SLCs transport amino acids in Na⁺-dependent or independent ways. Some of these transporters are heterodimerized with SLC3A1 or SLC3A2.

Figure 2

SLC1A3 and SLC1A4 role in cancer. SLC1A4 and SLC1A3 are transporters with tumor-promoting functions and enhance tumor cell proliferation and metastasis. Abbreviations: ETC electron transport chain, HIF hypoxia-inducible factor.

Figure 3

SLC1A5 role in cancer. SLC1A5 regulates the TCA cycle and ROS metabolism in cancer cells, enhances drug resistance, and prevents apoptosis and ferroptosis in augmenting tumor growth. Moreover, SLC1A5 affects the M2 polarization of macrophages, a function that could be suppressed by a combination of V9302 and anti-PD-1 therapy. Berberine, curcumin, and quercetin are among the natural products that effectively attenuate the function of SLC1A5 in cancer. Abbreviations: DDR1 Discoid protein domain receptor 1, GSH glutathione, mTORC1 mammalian target of rapamycin complex 1, TALDO1 Transaldolase 1, TCA tricarboxylic acid cycle.

Figure 4

SLC3A2 role in cancer. SLC3A2 is heterodimerized with some of the other SLCs, thus affecting several oncogenic pathways and molecules, including PI3K/AKT, mTOR, and MEK/ERK. SLC3A2 is involved in the regulation of ferroptosis, apoptosis, invasion, metastasis, and drug resistance. In the TME, SLC3A2 also increases the M2 polarization of macrophages and prevents the anti-cancer function of T cells. Abbreviations: FKBP1A FK506-binding protein 1A, HOXA13 Homeo box A13, IFNγ interferon-gamma, MMP metalloproteinase, ROCK Rho kinase, SCRIB Scribble, TAZ transcriptional coactivator with PDZ-binding motif, YAP1 Yes-associated protein 1, ZEB1 Zinc finger E-box-binding homeobox 1.

Figure 5

SLC7A1 and SLC7A2 role in cancer. SLC7A1 functions as a tumor promoter transporter by inhibiting apoptosis, regulating metabolism reprogramming, and increasing drug resistance. Abbreviations: mTORC1 mammalian target of rapamycin complex 1, RIOK3 Rio Kinase 3, SPOP speckle-type BTB/POZ.

Figure 6

SLC7A5 role in cancer. SLC7A5 activity affects mTOR and AKT function in enhancing tumor progression. By regulation of integrins, SLC7A5 also promotes metastasis of cancer cells, a function that can be suppressed by JPH203. In addition, metformin, BCH, and SKN103 are other inhibitors of SLC7A5, while YAP1/TAZ, MYC, and ATF4 augment the expression and function of SLC7A5. Enhancing angiogenesis, DNA damage repair mechanisms, and drug resistance in cancer cells are also mediated by the function of SLC7A5. Abbreviations: AFMID arylformamidase, BCH 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid, ROS reactive oxygen species, SLFN5 Schlafen family member 5, TAZ transcriptional coactivator with PDZ-binding motif, YAP1Yes-associated protein 1.

Figure 7

SLC7A11 role in cancer. SLC7A11 is an important component of defense against oxidative stress damage. SLC7A11 enhances tumor progression, prevents ferroptosis in cancer cells, and interacts with TME. Metformin, sulfasalazine, and erastin effectively prevent the function of SLC7A11 in cancer, thereby exerting anti-cancer function. Abbreviations: AMER1 APC Membrane Recruitment Protein 1, CAFs cancer-associated fibroblasts, CoQ ubiquinone, FSP1 ferroptosis suppressor protein 1, FTO Fat mass and obesity-associated protein, Keap1 Kelch-like ECH associated protein 1, PARP Poly (ADP-ribose) polymerase, SOX2 SRY (sex determining region Y)-box 2.

Figure 8

SLC43A1 and SLC43A2 role in cancer. SLC43A1 and SLC43A2 exert oncogenic function in cancer cells and TME. They interact with various molecules and pathways and their function is affected by therapeutic and oncogenic molecules. Abbreviations: eIF2a eukaryotic initiation factor 2a, ESPL1 Separase, GCN2 general control nonrepressed-2, mTORC1 mammalian target of rapamycin complex 1.