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Amino acid transporters (AATs) are membrane-bound transport proteins that mediate transfer of amino acids into and out of cells or cellular organelles. AATs have diverse functional roles ranging from neurotransmission to acid-base balance, intracellular energy metabolism, and anabolic and catabolic reactions. In cancer cells and diabetes, dysregulation of AATs leads to metabolic reprogramming, which changes intracellular amino acid levels, contributing to the pathogenesis of cancer, obesity and diabetes. Indeed, the neutral amino acid transporters (NATs) SLC7A5/LAT1 and SLC1A5/ASCT2 are likely involved in several human malignancies. However, a clinical therapy that directly targets AATs has not yet been developed. The purpose of this review is to highlight the structural and functional diversity of AATs, their diverse physiological roles in different tissues and organs, their wide-ranging implications in human diseases and the emerging strategies and tools that will be necessary to target AATs therapeutically.
AATs are transmembrane proteins that play vital roles by regulating energy metabolism, protein synthesis, gene expression, redox balance, signal transduction pathways and growth at the cellular and whole body levels.
Because of their central biological importance, alterations in the expression and function of AATs are linked to a wide range of pathologies, including neurodegenerative diseases, inborn errors of metabolism and chronic kidney diseases. AATs also participate in the secretion and release of hormones (e.g., insulin and glucagon), and their altered function is likely associated with pathogenesis of diabetes.
Dysregulation of AATs is implicated in autophagy and tumor cell proliferation via metabolic reprogramming, including the biosynthesis of proteins and nucleotides and the production of ATP and NADPH. Several AATs have been proposed as promising anticancer drug targets, e.g. SLC1A5, SLC7A5, SLC16A4, and SLC38A2.
Tumor cell AAT expression can be exploited for molecular imaging of tumors using transporter-specific positron-emission tomography (PET) probes. Recent PET studies have indicated a close relationship between the activation of various oncogenes and alterations of cellular metabolism via AATs. This novel approach will likely help in the future to optimize patient therapy management by improving monitoring of tumor grade staging, planning of best possible chemotherapeutic regimes and monitoring tumor response to therapy.
Many of the AATs are still understudied and uncovering their function and pathophysiological roles may unveil novel therapeutic strategies and drug discovery opportunities. Not too surprisingly, given that cancer therapeutics often represent amino acid mimetics, numerous AATs turn out to interact directly with these agents. Thus, AAT expression levels in tumor cells can determine drug efficacy by altering their delivery. Such knowledge will be helpful in the future to predict the outcome of cancer therapies.