title: Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development.
abstract: Glutamine is conditionally essential in cancer cells, being utilized as a carbon and nitrogen source for macromolecule production, as well as for anaplerotic reactions fuelling the tricarboxylic acid (TCA) cycle. In this study, we demonstrated that the glutamine transporter ASCT2 (SLC1A5) is highly expressed in prostate cancer patient samples. Using LNCaP and PC-3 prostate cancer cell lines, we showed that chemical or shRNA-mediated inhibition of ASCT2 function in vitro decreases glutamine uptake, cell cycle progression through E2F transcription factors, mTORC1 pathway activation and cell growth. Chemical inhibition also reduces basal oxygen consumption and fatty acid synthesis, showing that downstream metabolic function is reliant on ASCT2-mediated glutamine uptake. Furthermore, shRNA knockdown of ASCT2 in PC-3 cell xenografts significantly inhibits tumour growth and metastasis in vivo, associated with the down-regulation of E2F cell cycle pathway proteins. In conclusion, ASCT2-mediated glutamine uptake is essential for multiple pathways regulating the cell cycle and cell growth, and is therefore a putative therapeutic target in prostate cancer.
authors.affiliation: Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW, Australia.|Sydney Medical School, University of Sydney, NSW, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW, Australia.|Sydney Medical School, University of Sydney, NSW, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
authors.forename: Rae-Anne
authors.initials: RA
authors.lastname: Hardie
authors.affiliation: Discipline of Physiology, Bosch Institute and Charles Perkins Centre, University of Sydney, NSW, Australia.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hoy
authors.affiliation: Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW, Australia.|Sydney Medical School, University of Sydney, NSW, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: van Geldermalsen
authors.affiliation: Sydney Medical School, University of Sydney, NSW, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.|Bioinformatics, Centenary Institute, Camperdown, NSW, Australia.
authors.forename: Dadi
authors.initials: D
authors.lastname: Gao
authors.affiliation: Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Australia.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Sadowski
authors.affiliation: Discipline of Physiology, Bosch Institute and Charles Perkins Centre, University of Sydney, NSW, Australia.
authors.forename: Seher
authors.initials: S
authors.lastname: Balaban
authors.affiliation: Discipline of Physiology, Bosch Institute and Charles Perkins Centre, University of Sydney, NSW, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Schreuder
authors.affiliation: Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW, Australia.|Sydney Medical School, University of Sydney, NSW, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
authors.forename: Rajini
authors.initials: R
authors.lastname: Nagarajah
authors.affiliation: Sydney Medical School, University of Sydney, NSW, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
authors.forename: Justin J-L
authors.initials: JJ
authors.lastname: Wong
authors.affiliation: Sydney Medical School, University of Sydney, NSW, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Metierre
authors.affiliation: Sydney Medical School, University of Sydney, NSW, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Pinello
authors.affiliation: Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW, Australia.|Sydney Medical School, University of Sydney, NSW, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Otte
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Australia.
authors.forename: Melanie L
authors.initials: ML
authors.lastname: Lehman
authors.affiliation: Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Gleave
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Australia.
authors.forename: Colleen C
authors.initials: CC
authors.lastname: Nelson
authors.affiliation: Sydney Medical School, University of Sydney, NSW, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Bailey
authors.affiliation: Sydney Medical School, University of Sydney, NSW, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.|Bioinformatics, Centenary Institute, Camperdown, NSW, Australia.
authors.forename: William
authors.initials: W
authors.lastname: Ritchie
authors.affiliation: Sydney Medical School, University of Sydney, NSW, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.|Cell and Molecular Therapies, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: John E J
authors.initials: JE
authors.lastname: Rasko
authors.affiliation: Origins of Cancer Laboratory, Centenary Institute, Camperdown, NSW, Australia.|Sydney Medical School, University of Sydney, NSW, Australia.|Gene and Stem Cell Therapy Program, Centenary Institute, Camperdown, NSW, Australia.
authors.forename: Jeff
authors.initials: J
authors.lastname: Holst
mesh_terms: D026962:Amino Acid Transport System ASC / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D005973:Glutamine / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008819:Mice, Nude; D015778:Minor Histocompatibility Antigens; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D010100:Oxygen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D026962:Amino Acid Transport System ASC; D005227:Fatty Acids; D015778:Minor Histocompatibility Antigens; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; C420506:SLC1A5 protein, human; D005973:Glutamine; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D010100:Oxygen
keywords: ASCT2; SLC1A5; cell cycle; glutamine; metabolism; prostate cancer