Molecule Information

General Information of the Molecule (ID: Mol04089)

• Name: Alanine-serine-cysteine transporter 2 (ASCT2) ,Homo sapiens
• Synonyms: Baboon M7 virus receptor; RD114/simian type D retrovirus receptor; Sodium-dependent neutral amino acid transporter type 2; Solute carrier family 1 member 5
• Molecule Type: Protein
• Gene Name: SLC1A5
• Gene ID: 6510
• Location: chr19:46774883-46788594[-]
• Sequence:
  MVADPPRDSKGLAAAEPTANGGLALASIEDQGAAAGGYCGSRDQVRRCLRANLLVLLTVV
  AVVAGVALGLGVSGAGGALALGPERLSAFVFPGELLLRLLRMIILPLVVCSLIGGAASLD
  PGALGRLGAWALLFFLVTTLLASALGVGLALALQPGAASAAINASVGAAGSAENAPSKEV
  LDSFLDLARNIFPSNLVSAAFRSYSTTYEERNITGTRVKVPVGQEVEGMNILGLVVFAIV
  FGVALRKLGPEGELLIRFFNSFNEATMVLVSWIMWYAPVGIMFLVAGKIVEMEDVGLLFA
  RLGKYILCCLLGHAIHGLLVLPLIYFLFTRKNPYRFLWGIVTPLATAFGTSSSSATLPLM
  MKCVEENNGVAKHISRFILPIGATVNMDGAALFQCVAAVFIAQLSQQSLDFVKIITILVT
  ATASSVGAAGIPAGGVLTLAIILEAVNLPVDHISLILAVDWLVDRSCTVLNVEGDALGAG
  LLQNYVDRTESRSTEPELIQVKSELPLDPLPVPTEEGNPLLKHYRGPAGDATVASEKESV
  M
• 3D-structure: PDB ID: 8OUH; Classification: Protein transport; Method: Electron microscopy; Resolution: 2.62 Å
• Function: Sodium-coupled antiporter of neutral amino acids. In a tri- substrate transport cycle, exchanges neutral amino acids between the extracellular and intracellular compartments, coupled to the inward cotransport of at least one sodium ion (PubMed:17094966, PubMed:23756778, PubMed:26492990, PubMed:29872227, PubMed:34741534, PubMed:8702519). The preferred substrate is the essential amino acid L- glutamine, a precursor for biosynthesis of proteins, nucleotides and amine sugars as well as an alternative fuel for mitochondrial oxidative phosphorylation. Exchanges L-glutamine with other neutral amino acids such as L-serine, L-threonine and L-asparagine in a bidirectional way. Provides L-glutamine to proliferating stem and activated cells driving the metabolic switch toward cell differentiation (PubMed:23756778, PubMed:24953180). The transport cycle is usually pH-independent, with the exception of L-glutamate. Transports extracellular L-glutamate coupled to the cotransport of one proton and one sodium ion in exchange for intracellular L-glutamine counter-ion. May provide for L-glutamate uptake in glial cells regulating glutamine/glutamate cycle in the nervous system (PubMed:32733894). Can transport D-amino acids. Mediates D-serine release from the retinal glia potentially affecting NMDA receptor function in retinal neurons (PubMed:17094966). Displays sodium- and amino acid-dependent but uncoupled channel-like anion conductance with a preference SCN(-) >> NO3(-) > I(-) > Cl(-) (By similarity). Through binding of the fusogenic protein syncytin-1/ERVW-1 may mediate trophoblasts syncytialization, the spontaneous fusion of their plasma membranes, an essential process in placental development (PubMed:10708449, PubMed:23492904). .; (Microbial infection) Acts as a cell surface receptor for Feline endogenous virus RD114. .; (Microbial infection) Acts as a cell surface receptor for Baboon M7 endogenous virus. .; (Microbial infection) Acts as a cell surface receptor for type D simian retroviruses. .
• Uniprot ID: AAAT_HUMAN
• Ensembl ID: ENSG00000105281
• HGNC ID: HGNC:10943

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  MRAP: Metabolic Reprogramming via Altered Pathways

Drug Resistance Data Categorized by Drug

Approved Drug(s) 5 drug(s) in total

Cetuximab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Gastric adenocarcinoma [ICD-11: 2B72.0] [1]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Resistant Drug: Cetuximab
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BGC803 cells; Stomach; Homo sapiens (Human); CVCL_5334
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The expression of the key glutamine transporter alanine-serine-cysteine (ASC) transporter 2 (ASCT2; SLC1A5) was significantly higher in gastric carcinoma tissues and various gastric carcinoma cell lines than in normal gastric tissues and cells, as shown by immunohistochemistry and western blotting, while silencing ASCT2 significantly inhibited the viability and proliferation of gastric carcinoma cells. Consistent with previous studies, it was shown herein by MTT and EdU assays that cetuximab had a weak inhibitory effect on the cell viability of gastric carcinoma cells. However, inhibiting glutamine uptake by blockade of ASCT2 with l-gamma-glutamyl-p-nitroanilide (GPNA) significantly enhanced the inhibitory effect of cetuximab on suppressing the proliferation of gastric cancer both in vitro and in vivo.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Chondrosarcoma [ICD-11: 2B50.0] [2]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Chondrosarcoma [ICD-11: 2B50.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: JJ012 cells; Bone; Homo sapiens (Human); CVCL_D605
• In Vitro Model: SW-1353 cells; Brain; Homo sapiens (Human); CVCL_0543
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell colony formation assay
• Mechanism Description: The MEK, ERK, and NrF2 signaling pathways were shown to regulate AR-mediated alanine-serine-cysteine transporter 2 (ASCT2; also called SLC1A5) and glutaminase (GLS) expression as well as glutamine metabolism in cisplatin-resistant chondrosarcoma. The knockdown of AR expression in cisplatin-resistant chondrosarcoma cells was shown to reduce the expression of SLC1A5 and GLS in vivo. These results indicate that AR and glutamine metabolism are worth pursuing as therapeutic targets in dealing with cisplatin-resistant human chondrosarcoma.

Pimozide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Glioblastoma [ICD-11: 2A00.02] [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Resistant Drug: Pimozide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LN cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: LC-MS
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: These elevations are driven by SREBP-1, which we find upregulates the expression of ASCT2, a key glutamine transporter. Glutamine, in turn, intensifies SREBP-1 activation through the release of ammonia, creating a feedforward loop that amplifies both glutamine metabolism and lipid synthesis, leading to drug resistance. Disrupting this loop via pharmacological targeting of ASCT2 or glutaminase, in combination with pimozide, induces remarkable mitochondrial damage and oxidative stress, leading to GBM cell death in vitro and in vivo.

Prednisolone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Childhood acute lymphoblastic leukemia [ICD-11: 2B33.3] [4]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Childhood acute lymphoblastic leukemia [ICD-11: 2B33.3]
• Resistant Drug: Prednisolone
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Sup-B15 cells; Bone marrow; Homo sapiens (Human); CVCL_0103
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell proliferation assay; Cell apoptosis assay
• Mechanism Description: In an attempt to explore the potential therapeutic effect of inhibiting one of the hits from our analysis, we targeted the glutamine-glutamate-alpha-ketoglutarate axis by three different strategies, all of which impaired mitochondrial respiration and ATP production and induced apoptosis. Thereby, we report that prednisolone resistance may be accompanied by considerable rewiring of transcriptional and biosynthesis programs.

Sunitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Renal cell carcinoma [ICD-11: 2C90.0] [5]

• Metabolic Type: Redox metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Resistant Drug: Sunitinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 786-O cells; Kidney; Homo sapiens (Human); CVCL_1051
• In Vitro Model: ACHN cells; Pleural effusion; Homo sapiens (Human); CVCL_1067
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: In all three cell lines, qRT-PCR and Western blotting also showed overexpression of ASCT2 in sunitinib-resistant cells compared to sunitinib-sensitive cells (Figure 2a). When comparing the expression of ASCT2 among sunitinib-sensitive cells, ASCT2 was found to be highly expressed in 786-O compared to that in Caki-1 and ACHN (Figure 2a). Sunitinib-resistant cells had higher intracellular concentrations of glutamine metabolism (glutamine, glutamate, and alphaKG)

Disease Class: Renal cell carcinoma [ICD-11: 2C90.0] [5]

• Metabolic Type: Redox metabolism
• Resistant Disease: Renal cell carcinoma [ICD-11: 2C90.0]
• Resistant Drug: Sunitinib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Caki-1 cells; Kidney; Homo sapiens (Human); CVCL_0234
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: In all three cell lines, qRT-PCR and Western blotting also showed overexpression of ASCT2 in sunitinib-resistant cells compared to sunitinib-sensitive cells (Figure 2a). When comparing the expression of ASCT2 among sunitinib-sensitive cells, ASCT2 was found to be highly expressed in 786-O compared to that in Caki-1 and ACHN (Figure 3a). Sunitinib-resistant cells had higher intracellular concentrations of glutamine metabolism (glutamine, glutamate, and alphaKG)

Preclinical Drug(s) 1 drug(s) in total

l-gamma-Glutamyl-p-nitroanilide (GPNA)

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Disease Class: Gastric adenocarcinoma [ICD-11: 2B72.0] [1]

• Metabolic Type: Glutamine metabolism
• Sensitive Disease: Gastric adenocarcinoma [ICD-11: 2B72.0]
• Sensitive Drug: l-gamma-Glutamyl-p-nitroanilide (GPNA)
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: BGC803 cells; Stomach; Homo sapiens (Human); CVCL_5334
• In Vitro Model: GES-1 cells; Gastric; Homo sapiens (Human); CVCL_EQ22
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: The expression of the key glutamine transporter alanine-serine-cysteine (ASC) transporter 2 (ASCT2; SLC1A5) was significantly higher in gastric carcinoma tissues and various gastric carcinoma cell lines than in normal gastric tissues and cells, as shown by immunohistochemistry and western blotting, while silencing ASCT2 significantly inhibited the viability and proliferation of gastric carcinoma cells. Consistent with previous studies, it was shown herein by MTT and EdU assays that cetuximab had a weak inhibitory effect on the cell viability of gastric carcinoma cells. However, inhibiting glutamine uptake by blockade of ASCT2 with l-gamma-glutamyl-p-nitroanilide (GPNA) significantly enhanced the inhibitory effect of cetuximab on suppressing the proliferation of gastric cancer both in vitro and in vivo.

References

• Ref 1: Inhibition of Glutamine Uptake Improves the Efficacy of Cetuximab on Gastric Cancer. Integr Cancer Ther. 2021 Jan-Dec;20:15347354211045349.
• Ref 2: Glutamine metabolism controls amphiregulin-facilitated chemoresistance to cisplatin in human chondrosarcoma. Int J Biol Sci. 2023 Oct 9;19(16):5174-5186.
• Ref 3: Combinatorial targeting of glutamine metabolism and lysosomal-based lipid metabolism effectively suppresses glioblastoma. Cell Rep Med. 2024 Sep 17;5(9):101706.
• Ref 4: Targeting Glutaminolysis Shows Efficacy in Both Prednisolone-Sensitive and in Metabolically Rewired Prednisolone-Resistant B-Cell Childhood Acute Lymphoblastic Leukaemia Cells. Int J Mol Sci. 2023 Feb 8;24(4):3378.
• Ref 5: Elucidation and Regulation of Tyrosine Kinase Inhibitor Resistance in Renal Cell Carcinoma Cells from the Perspective of Glutamine Metabolism. Metabolites. 2024 Mar 19;14(3):170.