title: Targeting glutamine transport to suppress melanoma cell growth.
abstract: Amino acids, especially leucine and glutamine, are important for tumor cell growth, survival and metabolism. A range of different transporters deliver each specific amino acid into cells, some of which are increased in cancer. These amino acids consequently activate the mTORC1 pathway and drive cell cycle progression. The leucine transporter LAT1/4F2hc heterodimer assembles as part of a large complex with the glutamine transporter ASCT2 to transport amino acids. In this study, we show that the expression of LAT1 and ASCT2 is significantly increased in human melanoma samples and is present in both BRAF(WT) (C8161 and WM852) and BRAF(V600E) mutant (1205Lu and 451Lu) melanoma cell lines. While inhibition of LAT1 by BCH did not suppress melanoma cell growth, the ASCT2 inhibitor BenSer significantly reduced both leucine and glutamine transport in melanoma cells, leading to inhibition of mTORC1 signaling. Cell proliferation and cell cycle progression were significantly reduced in the presence of BenSer in melanoma cells in 2D and 3D cell culture. This included reduced expression of the cell cycle regulators CDK1 and UBE2C. The importance of ASCT2 expression in melanoma was confirmed by shRNA knockdown, which inhibited glutamine uptake, mTORC1 signaling and cell proliferation. Taken together, our study demonstrates that ASCT2-mediated glutamine transport is a potential therapeutic target for both BRAF(WT) and BRAF(V600E) melanoma.
authors: Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW, Australia; Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia; Sydney Medical School, University of Sydney, NSW, Australia.
authors: Qian
authors: Q
authors: Wang
authors: Kimberley A
authors: KA
authors: Beaumont
authors: Nicholas J
authors: NJ
authors: Otte
authors: Josep
authors: J
authors: Font
authors: Charles G
authors: CG
authors: Bailey
authors: Michelle
authors: M
authors: van Geldermalsen
authors: Danae M
authors: DM
authors: Sharp
authors: Jessamy C
authors: JC
authors: Tiffen
authors: Renae M
authors: RM
authors: Ryan
authors: Mika
authors: M
authors: Jormakka
authors: Nikolas K
authors: NK
authors: Haass
authors: John E J
authors: JE
authors: Rasko
authors: Jeff
authors: J
authors: Holst
mesh_terms: D026962:Amino Acid Transport System ASC / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D000598:Amino Acids, Cyclic / Q000494:pharmacology; D001593:Benzyl Compounds / Q000494:pharmacology; D001692:Biological Transport; D016203:CDC2 Protein Kinase / Q000096:biosynthesis; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D005973:Glutamine / Q000378:metabolism*; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000096:biosynthesis*; D007930:Leucine / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D015778:Minor Histocompatibility Antigens; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012694:Serine / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D018874:Spheroids, Cellular; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured; D044763:Ubiquitin-Conjugating Enzymes / Q000096:biosynthesis
chemical_list: D026962:Amino Acid Transport System ASC; D000598:Amino Acids, Cyclic; D001593:Benzyl Compounds; D002352:Carrier Proteins; D027283:Large Neutral Amino Acid-Transporter 1; D015778:Minor Histocompatibility Antigens; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; C420506:SLC1A5 protein, human; C521837:alpha-benzylserine; C037853:glutamine transport proteins; D005973:Glutamine; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid; D012694:Serine; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes; C482119:BRAF protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D007930:Leucine
keywords: ASCT2; LAT1; amino acid transport; mTORC1; melanoma