{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:32Z","timestamp":1787028452055,"version":"build-2736575974"},"reference-count":67,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T00:00:00Z","timestamp":1622678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006302","name":"Universidad de Alcal\u00e1","doi-asserted-by":"publisher","award":["CM\/JIN\/2019-019"],"award-info":[{"award-number":["CM\/JIN\/2019-019"]}],"id":[{"id":"10.13039\/501100006302","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministerio de Ciencia, Innovaci\u00f3n y Universidades of Spain","award":["SAF 2014-53639-R"],"award-info":[{"award-number":["SAF 2014-53639-R"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The dysregulation of autophagy is important in the development of many cancers, including thyroid cancer, where V600EBRAF is a main oncogene. Here, we analyse the effect of V600EBRAF inhibition on autophagy, the mechanisms involved in this regulation and the role of autophagy in cell survival of thyroid cancer cells. We reveal that the inhibition of V600EBRAF activity with its specific inhibitor PLX4720 or the depletion of its expression by siRNA induces autophagy in thyroid tumour cells. We show that V600EBRAF downregulation increases LKB1-AMPK signalling and decreases mTOR activity through a MEK\/ERK-dependent mechanism. Moreover, we demonstrate that PLX4720 activates ULK1 and increases autophagy through the activation of the AMPK-ULK1 pathway, but not by the inhibition of mTOR. In addition, we find that autophagy blockade decreases cell viability and sensitize thyroid cancer cells to V600EBRAF inhibition by PLX4720 treatment. Finally, we generate a thyroid xenograft model to demonstrate that autophagy inhibition synergistically enhances the anti-proliferative and pro-apoptotic effects of V600EBRAF inhibition in vivo. Collectively, we uncover a new role of AMPK in mediating the induction of cytoprotective autophagy by V600EBRAF inhibition. In addition, these data establish a rationale for designing an integrated therapy targeting V600EBRAF and the LKB1-AMPK-ULK1-autophagy axis for the treatment of V600EBRAF-positive thyroid tumours.<\/jats:p>","DOI":"10.3390\/ijms22116033","type":"journal-article","created":{"date-parts":[[2021,6,3]],"date-time":"2021-06-03T10:59:51Z","timestamp":1622717991000},"page":"6033","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["V600EBRAF Inhibition Induces Cytoprotective Autophagy through AMPK in Thyroid Cancer Cells"],"prefix":"10.3390","volume":"22","author":[{"given":"Eva","family":"Jim\u00e9nez-Mora","sequence":"first","affiliation":[{"name":"Departamento de Biolog\u00eda de Sistemas, Unidad de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Medicina, Campus Universitario, Universidad de Alcal\u00e1, Alcal\u00e1 de Henares, 28871 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7240-7200","authenticated-orcid":false,"given":"Beatriz","family":"Gallego","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda de Sistemas, Unidad de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Medicina, Campus Universitario, Universidad de Alcal\u00e1, Alcal\u00e1 de Henares, 28871 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergio","family":"D\u00edaz-Gago","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda de Sistemas, Unidad de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Medicina, Campus Universitario, Universidad de Alcal\u00e1, Alcal\u00e1 de Henares, 28871 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2245-3943","authenticated-orcid":false,"given":"Marina","family":"Lasa","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica-Instituto de Investigaciones Biom\u00e9dicas \u201cAlberto Sols\u201d, Universidad Aut\u00f3noma de Madrid-Consejo Superior de Investigaciones Cient\u00edficas, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Baquero","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda de Sistemas, Unidad de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Medicina, Campus Universitario, Universidad de Alcal\u00e1, Alcal\u00e1 de Henares, 28871 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7162-330X","authenticated-orcid":false,"given":"Antonio","family":"Chiloeches","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda de Sistemas, Unidad de Bioqu\u00edmica y Biolog\u00eda Molecular, Facultad de Medicina, Campus Universitario, Universidad de Alcal\u00e1, Alcal\u00e1 de Henares, 28871 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e208759","DOI":"10.1001\/jamanetworkopen.2020.8759","article-title":"Global Burden of Thyroid Cancer From 1990 to 2017","volume":"3","author":"Deng","year":"2020","journal-title":"JAMA Netw. 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