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      Pharmacologic inhibition of LAT1 predominantly suppresses transport of large neutral amino acids and downregulates global translation in cancer cells


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          L‐type amino acid transporter 1 (LAT1; SLC7A5), which preferentially transports large neutral amino acids, is highly upregulated in various cancers. LAT1 supplies cancer cells with amino acids as substrates for enhanced biosynthetic and bioenergetic reactions and stimulates signalling networks involved in the regulation of survival, growth and proliferation. LAT1 inhibitors show anti‐cancer effects and a representative compound, JPH203, is under clinical evaluation. However, pharmacological impacts of LAT1 inhibition on the cellular amino acid transport and the translational activity in cancer cells that are conceptually pivotal for its anti‐proliferative effect have not been elucidated yet. Here, we demonstrated that JPH203 drastically inhibits the transport of all the large neutral amino acids in pancreatic ductal adenocarcinoma cells. The inhibitory effects of JPH203 were observed even in competition with high concentrations of amino acids in a cell culture medium. The analyses of the nutrient‐sensing mTORC1 and GAAC pathways and the protein synthesis activity revealed that JPH203 downregulates the global translation. This study demonstrates a predominant contribution of LAT1 to the transport of large neutral amino acids in cancer cells and the suppression of protein synthesis by JPH203 supposed to underly its broad anti‐proliferative effects across various types of cancer cells.

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              The mechanistic target of rapamycin (mTOR) coordinates eukaryotic cell growth and metabolism with environmental inputs, including nutrients and growth factors. Extensive research over the past two decades has established a central role for mTOR in regulating many fundamental cell processes, from protein synthesis to autophagy, and deregulated mTOR signaling is implicated in the progression of cancer and diabetes, as well as the aging process. Here, we review recent advances in our understanding of mTOR function, regulation, and importance in mammalian physiology. We also highlight how the mTOR signaling network contributes to human disease and discuss the current and future prospects for therapeutically targeting mTOR in the clinic.

                Author and article information

                J Cell Mol Med
                J Cell Mol Med
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                07 September 2022
                October 2022
                : 26
                : 20 ( doiID: 10.1111/jcmm.v26.20 )
                : 5246-5256
                [ 1 ] Department of Bio‐system Pharmacology, Graduate School of Medicine Osaka University Osaka Japan
                [ 2 ] Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI) Osaka University Osaka Japan
                [ 3 ] Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences The University of Tokyo Tokyo Japan
                [ 4 ] J‐Pharma Co., Ltd Yokohama Japan
                Author notes
                [*] [* ] Correspondence

                Yoshikatsu Kanai and Ryuichi Ohgaki, Department of Bio‐system Pharmacology, Graduate School of Medicine, Osaka University, 2‐2 Yamadaoka, Suita, Osaka 565‐0871, Japan.

                Emails: ykanai@ 123456pharma1.med.osaka-u.ac.jp and ohgaki@ 123456pharma1.med.osaka-u.ac.jp

                Author information
                JCMM17553 JCMM-05-2022-124.R1
                © 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                : 12 August 2022
                : 20 May 2022
                : 30 August 2022
                Page count
                Figures: 5, Tables: 0, Pages: 11, Words: 7527
                Funded by: Japan Agency for Medical Research and Development , doi 10.13039/100009619;
                Award ID: JP20cm0106151
                Award ID: JP21cm0106151
                Funded by: Japan Society for the Promotion of Science , doi 10.13039/501100001691;
                Award ID: 19H03407
                Funded by: J‐Pharma Co., Ltd.
                Award ID: Collaborative Research Grant
                Funded by: Ministry of Education, Culture, Sports, Science and Technology , doi 10.13039/501100001700;
                Award ID: H25B7
                Funded by: National Institutes of Biomedical Innovation, Health and Nutrition , doi 10.13039/501100020300;
                Award ID: 12‐02
                Original Article
                Original Articles
                Custom metadata
                October 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.0 mode:remove_FC converted:17.10.2022

                Molecular medicine
                amino acid transporter,anti‐cancer agent,global translation,inhibitor,large neutral amino acids,lat1,pdac,slc7a5


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