{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T15:18:31Z","timestamp":1789139911852,"version":"build-2803163510"},"reference-count":58,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,11,22]],"date-time":"2017-11-22T00:00:00Z","timestamp":1511308800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16K09848"],"award-info":[{"award-number":["16K09848"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["16ak0101032h003"],"award-info":[{"award-number":["16ak0101032h003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:p>Adult T\u2010cell leukemia (<jats:styled-content style=\"fixed-case\">ATL<\/jats:styled-content>) has a poor prognosis as a result of severe immunosuppression and rapid tumor progression with resistance to conventional chemotherapy. Recent integrated\u2010genome analysis has revealed mutations in many genes involved in the T\u2010cell signaling pathway, suggesting that the aberration of this pathway is an important factor in <jats:styled-content style=\"fixed-case\">ATL<\/jats:styled-content> pathogenesis and <jats:styled-content style=\"fixed-case\">ATL<\/jats:styled-content>\u2010cell proliferation. We screened a si<jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content> library to examine signaling\u2010pathway functionality and found that the <jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3K\/Akt\/<jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> pathway is critical to <jats:styled-content style=\"fixed-case\">ATL<\/jats:styled-content>\u2010cell proliferation. We therefore investigated the effect of mammalian target of rapamycin (<jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content>) inhibitors, including the dual inhibitors <jats:styled-content style=\"fixed-case\">PP<\/jats:styled-content>242 and <jats:styled-content style=\"fixed-case\">AZD<\/jats:styled-content>8055 and the <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1 inhibitors rapamycin and everolimus, on human T\u2010cell leukemia virus type 1 (<jats:styled-content style=\"fixed-case\">HTLV<\/jats:styled-content>\u20101)\u2010infected\u2010cell and <jats:styled-content style=\"fixed-case\">ATL<\/jats:styled-content>\u2010cell lines. Both dual inhibitors inhibited the proliferation of all tested cell lines by inducing G1\u2010phase cell\u2010cycle arrest and subsequent cell apoptosis, whereas the effects of the 2 <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1 inhibitors were limited, as they did not induce cell apoptosis. In the <jats:styled-content style=\"fixed-case\">ATL<\/jats:styled-content>\u2010cell lines and in the primary <jats:styled-content style=\"fixed-case\">ATL<\/jats:styled-content> samples, both dual inhibitors inhibited phosphorylation of <jats:styled-content style=\"fixed-case\">AKT<\/jats:styled-content> at serine\u2010473, a target of <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>2, as well as that of S6K, whereas the <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1 inhibitors only inhibited <jats:styled-content style=\"fixed-case\">mTORC<\/jats:styled-content>1. Furthermore, <jats:styled-content style=\"fixed-case\">AZD<\/jats:styled-content>8055 more significantly inhibited the in\u00a0vivo growth of the <jats:styled-content style=\"fixed-case\">ATL<\/jats:styled-content>\u2010cell xenografts than did everolimus. These results indicate that the <jats:styled-content style=\"fixed-case\">PI<\/jats:styled-content>3K\/<jats:styled-content style=\"fixed-case\">mTOR<\/jats:styled-content> pathway is critical to <jats:styled-content style=\"fixed-case\">ATL<\/jats:styled-content>\u2010cell proliferation and might thus be a new therapeutic target in ATL.<\/jats:p>","DOI":"10.1111\/cas.13431","type":"journal-article","created":{"date-parts":[[2017,10,27]],"date-time":"2017-10-27T14:56:36Z","timestamp":1509116196000},"page":"103-111","source":"Crossref","is-referenced-by-count":27,"title":["Dual inhibition of the <scp>mTORC<\/scp>1 and <scp>mTORC<\/scp>2 signaling pathways is a promising therapeutic target for adult T\u2010cell leukemia"],"prefix":"10.1111","volume":"109","author":[{"given":"Takahito","family":"Kawata","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Tada","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8733-8458","authenticated-orcid":false,"given":"Masayuki","family":"Kobayashi","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Takiuchi","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumie","family":"Iwai","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Sakurada","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakatsu","family":"Hishizawa","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kotaro","family":"Shirakawa","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keisuke","family":"Shindo","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Sato","sequence":"additional","affiliation":[{"name":"Pathogen Genomics Center National Institute of Infectious Diseases Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akifumi","family":"Takaori\u2010Kondo","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology Graduate School of Medicine Kyoto University Kyoto Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,11,22]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.78.10.6476"},{"key":"e_1_2_7_3_1","first-page":"285","article-title":"A retrovirus from human leukemia cell lines: its isolation, characterization, and implication in human adult T\u2010cell leukemia (ATL)","volume":"12","author":"Yoshida M","year":"1982","journal-title":"Princess Takamatsu Symp"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V50.3.481.481"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2009-10-247510"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M510598200"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2006.08.001"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/3.8.761"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-5-76"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/348245a0"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.20007"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.18.9389-9397.2002"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3415"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12185-011-0937-1"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0507631103"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-6-71"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2013.181"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1080\/10428190802709446"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.25742"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.017"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11523-011-0167-8"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1106148"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.139"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-1751"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2091"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-11-393934"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-03-342394"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-12-399519"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2011.30"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-05-285726"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2011.339"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-8722-6-18"},{"key":"e_1_2_7_33_1","first-page":"95","article-title":"Torin2 potentiates anticancer effects on adult T\u2010cell leukemia\/lymphoma by inhibiting mammalian target of rapamycin","volume":"36","author":"Watanabe T","year":"2016","journal-title":"Anticancer Res"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.162.6.2169"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.176.5.1265"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V86.6.2350.bloodjournal8662350"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2004.tb03224.x"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.77.12.7415"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2007.05.173"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0085762"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V82.8.2501.2501"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1400203"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204091"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2010.170"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1362"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1199498"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1199484"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-2925"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M508361200"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.684746"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2011.02123.x"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2007.09.003"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coviro.2013.08.010"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep12841"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4393"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-11-0850"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2012.368"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2017.01.035"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.26409"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcas.13431","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.13431","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T05:40:32Z","timestamp":1693978832000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.13431"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,22]]},"references-count":58,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2018,1]]}},"alternative-id":["10.1111\/cas.13431"],"URL":"https:\/\/doi.org\/10.1111\/cas.13431","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,22]]}}}