{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T20:21:52Z","timestamp":1791404512016,"version":"4.3.3"},"reference-count":50,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2016,11,25]],"date-time":"2016-11-25T00:00:00Z","timestamp":1480032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003785","name":"Guangdong Medical Research Foundation","doi-asserted-by":"publisher","award":["B2014273"],"award-info":[{"award-number":["B2014273"]}],"id":[{"id":"10.13039\/501100003785","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81570772"],"award-info":[{"award-number":["81570772"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer Science"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:p>\n                    Metformin is an oral biguanide commonly used for treating type\n                    <jats:styled-content style=\"fixed-case\">II<\/jats:styled-content>\n                    diabetes and has recently been reported to possess antiproliferative properties that can be exploited for the prevention and treatment of a variety of cancers. The mechanisms underlying this effect have not been fully elucidated. Our study shows a marked loss 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                    ) phosphorylation and nuclear human Forkhead box O1 (\n                    <jats:styled-content style=\"fixed-case\">FOXO<\/jats:styled-content>\n                    1) protein in estrogen\u2010dependent endometrial cancer (\n                    <jats:styled-content style=\"fixed-case\">EC<\/jats:styled-content>\n                    ) tumors compared to normal control endometrium. Metformin treatment suppressed\n                    <jats:styled-content style=\"fixed-case\">EC<\/jats:styled-content>\n                    cell growth in a time\u2010dependent manner\n                    <jats:italic>in vitro<\/jats:italic>\n                    ; this effect was cancelled by cotreatment with an\n                    <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>\n                    inhibitor, compound C. Metformin decreased\n                    <jats:styled-content style=\"fixed-case\">FOXO<\/jats:styled-content>\n                    1 phosphorylation and increased\n                    <jats:styled-content style=\"fixed-case\">FOXO<\/jats:styled-content>\n                    1 nuclear localization in Ishikawa and\n                    <jats:styled-content style=\"fixed-case\">HEC<\/jats:styled-content>\n                    \u20101B cells, with non\u2010significant increase in\n                    <jats:styled-content style=\"fixed-case\">FOXO<\/jats:styled-content>\n                    1\n                    <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>\n                    expression. Moreover, compound C blocked the metformin\u2010induced changes of\n                    <jats:styled-content style=\"fixed-case\">FOXO<\/jats:styled-content>\n                    1 and its phosphorylation protein, suggesting that metformin upregulated\n                    <jats:styled-content style=\"fixed-case\">FOXO<\/jats:styled-content>\n                    1 activity by\n                    <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>\n                    activation. Similar results were obtained after treatment with insulin. In addition, transfection with si\n                    <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\n                    for\n                    <jats:styled-content style=\"fixed-case\">FOXO<\/jats:styled-content>\n                    1 cancelled metformin\u2010inhibited cell growth, indicating that\n                    <jats:styled-content style=\"fixed-case\">FOXO<\/jats:styled-content>\n                    1 mediated metformin to inhibit\n                    <jats:styled-content style=\"fixed-case\">EC<\/jats:styled-content>\n                    cell proliferation. A xenograft mouse model further revealed that metformin suppressed\n                    <jats:styled-content style=\"fixed-case\">HEC<\/jats:styled-content>\n                    \u20101B tumor growth, accompanied by downregulated ki\u201067 and upregulated\n                    <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>\n                    phosphorylation and nuclear\n                    <jats:styled-content style=\"fixed-case\">FOXO<\/jats:styled-content>\n                    1 protein. Taken together, these data provide a novel mechanism of antineoplastic effect for metformin through the regulation of\n                    <jats:styled-content style=\"fixed-case\">FOXO<\/jats:styled-content>\n                    1, and suggest that the\n                    <jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>\n                    \u2013\n                    <jats:styled-content style=\"fixed-case\">FOXO<\/jats:styled-content>\n                    1 pathway may be a therapeutic target to the development of new antineoplastic drugs.\n                  <\/jats:p>","DOI":"10.1111\/cas.13083","type":"journal-article","created":{"date-parts":[[2016,9,16]],"date-time":"2016-09-16T10:12:52Z","timestamp":1474020772000},"page":"1806-1817","source":"Crossref","is-referenced-by-count":47,"title":["Metformin inhibits estrogen\u2010dependent endometrial cancer cell growth by activating the\n                    <scp>AMPK<\/scp>\n                    \u2013\n           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