title: LAT1 is a putative therapeutic target in endometrioid endometrial carcinoma.
abstract: l-type amino acid transporters (LAT1-4) are expressed in various cancer types and are involved in the uptake of essential amino acids such as leucine. Here we investigated the expression of LAT1-4 in endometrial adenocarcinoma and evaluated the contribution of LATs to endometrial cancer cell growth. Analysis of human gene expression data showed that all four LAT family members are expressed in endometrial adenocarcinomas. LAT1 was the most highly expressed, and showed a significant increase in both serous and endometrioid subtypes compared to normal endometrium. Endometrioid patients with the highest LAT1 levels exhibited the lowest disease-free survival. The pan-LAT inhibitor BCH led to a significant decrease in cell growth and spheroid area in four endometrial cancer cell lines tested in vitro. Knockdown of LAT1 by shRNA inhibited cell growth in HEC1A and Ishikawa cells, as well as inhibiting spheroid area in HEC1A cells. These data show that LAT1 plays an important role in regulating the uptake of essential amino acids such as leucine into endometrial cancer cells. Increased ability of BCH compared to LAT1 shRNA at inhibiting Ishikawa spheroid area suggests that other LAT family members may also contribute to cell growth. LAT1 inhibition may offer an effective therapeutic strategy in endometrial cancer patients whose tumours exhibit high LAT1 expression.
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Amy D
authors.initials: AD
authors.lastname: Marshall
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Origins of Cancer Program, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: van Geldermalsen
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Origins of Cancer Program, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Otte
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: Lyndal A
authors.initials: LA
authors.lastname: Anderson
authors.affiliation: Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: Trina
authors.initials: T
authors.lastname: Lum
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Vellozzi
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Origins of Cancer Program, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia.
authors.forename: Blake K
authors.initials: BK
authors.lastname: Zhang
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Annora
authors.initials: A
authors.lastname: Thoeng
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Origins of Cancer Program, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Gene and Stem Cell Therapy Program, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia.|Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.|Cell and Molecular Therapies, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.
authors.forename: John E J
authors.initials: JE
authors.lastname: Rasko
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. j.holst@centenary.org.au.|Origins of Cancer Program, Centenary Institute, University of Sydney, Camperdown, New South Wales, Australia. j.holst@centenary.org.au.
authors.forename: Jeff
authors.initials: J
authors.lastname: Holst
mesh_terms: D000598:Amino Acids, Cyclic / Q000494:pharmacology; D018269:Carcinoma, Endometrioid / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000096:biosynthesis* / Q000235:genetics; D058990:Molecular Targeted Therapy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D018874:Spheroids, Cellular
chemical_list: D000598:Amino Acids, Cyclic; D027283:Large Neutral Amino Acid-Transporter 1; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C006504:2-aminobicyclo(2,2,1)heptane-2-carboxylic acid
keywords: BCH; LAT1; endometrial carcinoma; endometrioid adenocarcinoma; l-type amino acid transporters