{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:46:18Z","timestamp":1787013978383,"version":"build-2736575974"},"reference-count":51,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2017,12,7]],"date-time":"2017-12-07T00:00:00Z","timestamp":1512604800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001700","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>\n                    Tyrosine kinase inhibitors (\n                    <jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>\n                    ), including imatinib (\n                    <jats:styled-content style=\"fixed-case\">IM<\/jats:styled-content>\n                    ), improve the outcome of\n                    <jats:styled-content style=\"fixed-case\">CML<\/jats:styled-content>\n                    therapy. However,\n                    <jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>\n                    treatment is long\u2010term and can induce resistance to\n                    <jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>\n                    , which often leads to a poor clinical outcome in\n                    <jats:styled-content style=\"fixed-case\">CML<\/jats:styled-content>\n                    patients. Here, we examined the effect of continuous\n                    <jats:styled-content style=\"fixed-case\">IM<\/jats:styled-content>\n                    exposure on intracellular energy metabolism in K562 cells, a human Philadelphia chromosome\u2010positive\n                    <jats:styled-content style=\"fixed-case\">CML<\/jats:styled-content>\n                    cell line, and its subsequent sensitivity to anti\u2010cancer agents. Contrary to our expectations, we found that continuous\n                    <jats:styled-content style=\"fixed-case\">IM<\/jats:styled-content>\n                    exposure increased sensitivity to\n                    <jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>\n                    . Cancer energy metabolism, characterized by abnormal glycolysis, is linked to cancer cell survival. Interestingly, glycolytic activity was suppressed by continuous exposure to\n                    <jats:styled-content style=\"fixed-case\">IM<\/jats:styled-content>\n                    , and autophagy increased to maintain cell viability by compensating for glycolytic suppression. Notably, increased sensitivity to\n                    <jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>\n                    was not caused by glycolytic inhibition but by altered intracellular signaling, causing glycolytic suppression and increased autophagy, as evidenced by suppression of p70 S6 kinase 1 (S6K1) and activation of\n                    <jats:styled-content style=\"fixed-case\">AMP<\/jats:styled-content>\n                    \u2010activated protein kinase (\n                    <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>\n                    ). Using another human\n                    <jats:styled-content style=\"fixed-case\">CML<\/jats:styled-content>\n                    cell line (\n                    <jats:styled-content style=\"fixed-case\">KCL<\/jats:styled-content>\n                    22 cells) and\n                    <jats:styled-content style=\"fixed-case\">BCR<\/jats:styled-content>\n                    \/\n                    <jats:styled-content style=\"fixed-case\">ABL<\/jats:styled-content>\n                    + Ba\/F3 cells (mimicking Philadelphia chromosome\u2010positive\n                    <jats:styled-content style=\"fixed-case\">CML<\/jats:styled-content>\n                    cells) confirmed that suppressing S6K1 and activating\n                    <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>\n                    increased sensitivity to\n                    <jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>\n                    . Furthermore, suppressing S6K1 and activating\n                    <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>\n                    had a synergistic anti\u2010cancer effect by inhibiting autophagy in the presence of\n                    <jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>\n                    . The present study provides new insight into the importance of signaling pathways that affect cellular energy metabolism, and suggests that co\u2010treatment with\u00a0agents that disrupt energy metabolic signaling (using S6K1 suppressors and\n                    <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>\n                    activators) plus blockade of autophagy may be strategies for\n                    <jats:styled-content style=\"fixed-case\">TKI<\/jats:styled-content>\n                    \u2010based\n                    <jats:styled-content style=\"fixed-case\">CML<\/jats:styled-content>\n                    therapy.\n                  <\/jats:p>","DOI":"10.1111\/cas.13442","type":"journal-article","created":{"date-parts":[[2017,11,9]],"date-time":"2017-11-09T14:02:39Z","timestamp":1510236159000},"page":"121-131","source":"Crossref","is-referenced-by-count":25,"title":["Altered intracellular signaling by imatinib increases the anti\u2010cancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia cells"],"prefix":"10.1111","volume":"109","author":[{"given":"Takuya","family":"Hirao","sequence":"first","affiliation":[{"name":"Laboratory of Biopharmaceutics Graduate School of Pharmaceutical Sciences Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Medical Mycology Research Center Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megumi","family":"Kikuya","sequence":"additional","affiliation":[{"name":"Laboratory of Biopharmaceutics Graduate School of Pharmaceutical Sciences Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroji","family":"Chibana","sequence":"additional","affiliation":[{"name":"Medical Mycology Research Center Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kousei","family":"Ito","sequence":"additional","affiliation":[{"name":"Laboratory of Biopharmaceutics Graduate School of Pharmaceutical Sciences Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2821-0651","authenticated-orcid":false,"given":"Shigeki","family":"Aoki","sequence":"additional","affiliation":[{"name":"Laboratory of Biopharmaceutics Graduate School of Pharmaceutical Sciences Chiba University Chiba Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,12,7]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199904293401706"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111501200"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-03-144790"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0596-561"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1062538"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2006.07.010"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403426"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-12-3659"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-1516"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24247"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1272\/jnms.73.178"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2403898"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.7.2008"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0602402103"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.2001.02428.x"},{"key":"e_1_2_8_17_1","doi-asserted-by":"crossref","first-page":"37747","DOI":"10.1074\/jbc.M105796200","article-title":"Gleevec (STI571) influences metabolic enzyme activities and glucose carbon flow toward nucleic acid and fatty acid synthesis in myeloid tumor cells","volume":"276","author":"Boren J","year":"2001","journal-title":"J Biol Chem"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-04-0039"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.67"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1160809"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-03-3294"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-007-9376-3"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.04.098"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/jmicro\/dfr032"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/jmicro\/dfp013"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/jmicro\/dfw016"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6604946"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2011.123"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7676"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12013-014-0434-2"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2012.70"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI13505"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.201300402"},{"key":"e_1_2_8_34_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/603980"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2008.337"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-050008"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.14310\/horm.2002.1288"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.23.9312"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.171301998"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.4161\/cc.25920"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.leukres.2009.07.012"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-332783"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2016.6094"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2015.11.020"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.genet.39.110304.095751"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/jhg.2013.57"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.4161\/epi.5.7.12662"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.12.012"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-1560"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1182\/asheducation-2008.1.427"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1900\/RDS.2013.10.228"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj3480607"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcas.13442","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/api.wiley.com\/onlinelibrary\/chorus\/v1\/articles\/10.1111%2Fcas.13442","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.13442","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T01:41:07Z","timestamp":1693964467000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.13442"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,12,7]]},"references-count":51,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2018,1]]}},"alternative-id":["10.1111\/cas.13442"],"URL":"https:\/\/doi.org\/10.1111\/cas.13442","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,12,7]]}}}