Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma
L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a speci...
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| Veröffentlicht in: | Scientific reports 2020-01, Vol.10 (1), p.1292-1292, Article 1292 |
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| creator | Maimaiti, Maihulan Sakamoto, Shinichi Yamada, Yasutaka Sugiura, Masahiro Rii, Junryo Takeuchi, Nobuyoshi Imamura, Yusuke Furihata, Tomomi Ando, Keisuke Higuchi, Kosuke Xu, Minhui Sazuka, Tomokazu Nakamura, Kazuyoshi Kaneda, Atsushi Kanai, Yoshikatsu Kyprianou, Natasha Ikehara, Yuzuru Anzai, Naohiko Ichikawa, Tomohiko |
| description | L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK / Erk, AKT, p70S6K and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (P = 0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment. |
| doi_str_mv | 10.1038/s41598-020-58136-x |
| format | Article |
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Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK / Erk, AKT, p70S6K and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (P = 0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-020-58136-x</identifier><identifier>PMID: 31992742</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>45 ; 45/91 ; 59 ; 631/67/1059/99 ; 631/67/1680 ; 631/67/589/1336 ; 64 ; 692/4025/1334 ; 82 ; 82/29 ; 96/1 ; 96/31 ; AKT protein ; Amino acids ; Benzoxazoles - pharmacology ; Bladder cancer ; Cell Line, Tumor ; Cell migration ; Disease-Free Survival ; Extracellular Signal-Regulated MAP Kinases - metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Humanities and Social Sciences ; Humans ; Insulin ; Insulin-like growth factor-binding protein 5 ; Invasiveness ; Kinases ; Large Neutral Amino Acid-Transporter 1 - biosynthesis ; Leucine ; Male ; MAP kinase ; MAP Kinase Signaling System ; multidisciplinary ; Multivariate analysis ; Neoplasm Proteins - antagonists & inhibitors ; Neoplasm Proteins - biosynthesis ; Phosphorylation ; Ribonucleic acid ; RNA ; Science ; Science (multidisciplinary) ; Signal transduction ; Survival Rate ; TOR protein ; TOR Serine-Threonine Kinases - metabolism ; Tyrosine - analogs & derivatives ; Tyrosine - pharmacology ; Urinary Bladder Neoplasms - drug therapy ; Urinary Bladder Neoplasms - metabolism ; Urinary Bladder Neoplasms - microbiology ; Urinary Bladder Neoplasms - pathology</subject><ispartof>Scientific reports, 2020-01, Vol.10 (1), p.1292-1292, Article 1292</ispartof><rights>The Author(s) 2020</rights><rights>This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c540t-83f260ee5c852501d109e626ab998fee965eb7bdaaf8d0fec28e9be34e460a9b3</citedby><cites>FETCH-LOGICAL-c540t-83f260ee5c852501d109e626ab998fee965eb7bdaaf8d0fec28e9be34e460a9b3</cites><orcidid>0000-0002-0070-1590 ; 0000-0002-6980-5515</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987139/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987139/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27903,27904,41099,42168,51554,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31992742$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Maimaiti, Maihulan</creatorcontrib><creatorcontrib>Sakamoto, Shinichi</creatorcontrib><creatorcontrib>Yamada, Yasutaka</creatorcontrib><creatorcontrib>Sugiura, Masahiro</creatorcontrib><creatorcontrib>Rii, Junryo</creatorcontrib><creatorcontrib>Takeuchi, Nobuyoshi</creatorcontrib><creatorcontrib>Imamura, Yusuke</creatorcontrib><creatorcontrib>Furihata, Tomomi</creatorcontrib><creatorcontrib>Ando, Keisuke</creatorcontrib><creatorcontrib>Higuchi, Kosuke</creatorcontrib><creatorcontrib>Xu, Minhui</creatorcontrib><creatorcontrib>Sazuka, Tomokazu</creatorcontrib><creatorcontrib>Nakamura, Kazuyoshi</creatorcontrib><creatorcontrib>Kaneda, Atsushi</creatorcontrib><creatorcontrib>Kanai, Yoshikatsu</creatorcontrib><creatorcontrib>Kyprianou, Natasha</creatorcontrib><creatorcontrib>Ikehara, Yuzuru</creatorcontrib><creatorcontrib>Anzai, Naohiko</creatorcontrib><creatorcontrib>Ichikawa, Tomohiko</creatorcontrib><title>Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK / Erk, AKT, p70S6K and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (P = 0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment.</description><subject>45</subject><subject>45/91</subject><subject>59</subject><subject>631/67/1059/99</subject><subject>631/67/1680</subject><subject>631/67/589/1336</subject><subject>64</subject><subject>692/4025/1334</subject><subject>82</subject><subject>82/29</subject><subject>96/1</subject><subject>96/31</subject><subject>AKT protein</subject><subject>Amino acids</subject><subject>Benzoxazoles - pharmacology</subject><subject>Bladder cancer</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Disease-Free Survival</subject><subject>Extracellular Signal-Regulated MAP Kinases - metabolism</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Insulin</subject><subject>Insulin-like growth factor-binding protein 5</subject><subject>Invasiveness</subject><subject>Kinases</subject><subject>Large Neutral Amino Acid-Transporter 1 - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Maimaiti, Maihulan</au><au>Sakamoto, Shinichi</au><au>Yamada, Yasutaka</au><au>Sugiura, Masahiro</au><au>Rii, Junryo</au><au>Takeuchi, Nobuyoshi</au><au>Imamura, Yusuke</au><au>Furihata, Tomomi</au><au>Ando, Keisuke</au><au>Higuchi, Kosuke</au><au>Xu, Minhui</au><au>Sazuka, Tomokazu</au><au>Nakamura, Kazuyoshi</au><au>Kaneda, Atsushi</au><au>Kanai, Yoshikatsu</au><au>Kyprianou, Natasha</au><au>Ikehara, Yuzuru</au><au>Anzai, Naohiko</au><au>Ichikawa, Tomohiko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2020-01-28</date><risdate>2020</risdate><volume>10</volume><issue>1</issue><spage>1292</spage><epage>1292</epage><pages>1292-1292</pages><artnum>1292</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK / Erk, AKT, p70S6K and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (P = 0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31992742</pmid><doi>10.1038/s41598-020-58136-x</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-0070-1590</orcidid><orcidid>https://orcid.org/0000-0002-6980-5515</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 45 45/91 59 631/67/1059/99 631/67/1680 631/67/589/1336 64 692/4025/1334 82 82/29 96/1 96/31 AKT protein Amino acids Benzoxazoles - pharmacology Bladder cancer Cell Line, Tumor Cell migration Disease-Free Survival Extracellular Signal-Regulated MAP Kinases - metabolism Female Gene Expression Regulation, Neoplastic Humanities and Social Sciences Humans Insulin Insulin-like growth factor-binding protein 5 Invasiveness Kinases Large Neutral Amino Acid-Transporter 1 - biosynthesis Leucine Male MAP kinase MAP Kinase Signaling System multidisciplinary Multivariate analysis Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - biosynthesis Phosphorylation Ribonucleic acid RNA Science Science (multidisciplinary) Signal transduction Survival Rate TOR protein TOR Serine-Threonine Kinases - metabolism Tyrosine - analogs & derivatives Tyrosine - pharmacology Urinary Bladder Neoplasms - drug therapy Urinary Bladder Neoplasms - metabolism Urinary Bladder Neoplasms - microbiology Urinary Bladder Neoplasms - pathology |
| title | Expression of L-type amino acid transporter 1 as a molecular target for prognostic and therapeutic indicators in bladder carcinoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-27T16%3A48%3A45IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Expression%20of%20L-type%20amino%20acid%20transporter%201%20as%20a%20molecular%20target%20for%20prognostic%20and%20therapeutic%20indicators%20in%20bladder%20carcinoma&rft.jtitle=Scientific%20reports&rft.au=Maimaiti,%20Maihulan&rft.date=2020-01-28&rft.volume=10&rft.issue=1&rft.spage=1292&rft.epage=1292&rft.pages=1292-1292&rft.artnum=1292&rft.issn=2045-2322&rft.eissn=2045-2322&rft_id=info:doi/10.1038/s41598-020-58136-x&rft_dat=%3Cproquest_pubme%3E2348109333%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2348109333&rft_id=info:pmid/31992742&rfr_iscdi=true |