Target the human Alanine/Serine/Cysteine Transporter 2(ASCT2): Achievement and Future for Novel Cancer Therapy. (August 2020)

• Record Type: Journal Article
• Authors: Jiang, Hongli; Zhang, Ning; Tang, Tongzhong; Feng, Feng; Sun, Haopeng; Qu, Wei
• Is Part Of: Pharmacological research. Volume 158(2020)
• Publication Date: 2020-08
• Subjects: TCA tricarboxylic acid -- STAT3 signal transducer and activator of transcription 3 -- GLS Glutaminase -- α-KG α-ketoglutarate -- GDH glutamate dehydrogenase -- OAA oxaloacetate -- SLC solute carried -- LAT1 L-type amino acid transporter -- mTORC1 mammalian target of rapamycin complex 1 -- AML acute myeloid leukaemia -- HCC Hepatocellular Carcnoma -- NSCLC non-small cell lung cancer -- CDK1 cyclin-dependent kinase 1 -- CDC20 cell division cycle20 -- UBE2C ubiquitin-conjugating enzyme E2C -- GC gastric cancer -- CRC colorectal cancer -- TCR T cell receptor -- CARMA1 membrane-associated guanylate kinase protein containing caspase recruitment domain 1 -- RCC renal cell carcinoma -- FXR the farnesoid receptor -- 4EBP1 eukaryotic initiation factor 4E binding protein 1 -- S6K1 ribosomal protein S6 kinase 1 -- SNX27 sorting nexin-27 -- GPCRs G-protein-coupled receptors -- GLUT1 glucose transporter 1 -- IL4 interleukin-4 -- ER estrogen receptor -- HER2 human epidermal growth factor receptor 2 -- PPARδ peroxisome-proliferator-activated receptor δ -- MeCP2 methyl-CpG-binding protein 2 -- DNMT methyltransferase -- EGF epidermal growth factor -- EGFR EGF receptor -- ERK extracellular regulated kinase -- PI3K phosphatidyl inositol-3 kinase -- SGK serine/threonine-protein kinases -- PKB protein kinase -- T1R1 transport inhibitor response protein 1 -- HTS high-throughput screen -- PET positron emission tomography -- PDX patient-derived xenograft -- DARTS drug affinity responsive target stability -- PG proline-glycine -- LTP long-term potentiation -- MAb monoclonal antibody -- GPNA L-γ-glutamyl-p-nitroanilide -- DTE dithioerythritol -- SERT the serotonin transporter -- PTM post-translational modifications; Benzyl-serine (PubChem CID: 78457) -- Benzyl-cysteine (PubChem CID: 101603455) -- L-γ-glutamyl-p-nitroanilide (GPNA, PubChem CID: 558754) -- V-9302 (PubChem CID:127035871) -- γ-2-fluorobenzyl proline (PubChem CID:2761966) -- L-4Cl proline-glycine (PubChem CID: 738019) -- 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5, 6, 7, 8-tetrahydro-4H-chromene-3-carbonitrile, UCPH101(PubChem CID: 25223366) -- DTE (PubChem CID: 439352); Cancer -- Glutamine transporter -- ASCT2 -- Inhibitors; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2020.104844
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: Highlights: Blockade ASCT2 glutamine transport may potentially abolish glutamine metabolism and represent a more efficacious strategy. Comprehension of antitumor functions and possible regulatory mechanisms is powerful in the characterization of ASCT2 biochemical functions and the design of modulators. The direct inhibition of ASCT2 is a promising strategy. We proposed that, a new binding cavity of ASCT2 triggers downstream signal transduction in allosteric ways. Identification of the pharmacological and molecular mechanisms of ASCT2 provides the basis for the rational discovery and design of the novel ASCT2 antagonist with improved potency and selectivity. Abstract: Glutamine metabolism, described as major energy and building blocks supply to cell growth, has gained great attention. Alanine-Serine-Cysteine Transporter (ASCT2), which belongs to solute carried (SLC) family transporters and is encoded by the SLC1A5 gene serves as a significant role for glutamine transport. Indeed, ASCT2 is often overexpressed in highly proliferative cancer cells to fulfill enhanced glutamine demand. So far, ASCT2 has been proved to be a significant target during the carcinogenesis process, and emerging evidence reveals that ASCT2 inhibitors can provide a benefit strategy for cancer therapy. Herein, we describe the structure of ASCT2, and summarize its related regulatory factors which are associated with antitumor activity. Moreover, this review article highlights the remarkable reform of discovery and development for ASCT2 inhibitors. On the basis of case studies, our perspectives for targeting ASCT2 and development of ASCT2 antagonist are discussed in the final part.