Paeonol induces cytoprotective autophagy via blocking the Akt/mTOR pathway in ovarian cancer cells
Identifieur interne : 000068 ( Pmc/Curation ); précédent : 000067; suivant : 000069Paeonol induces cytoprotective autophagy via blocking the Akt/mTOR pathway in ovarian cancer cells
Auteurs : Likun Gao ; Zhi Wang ; Danhua Lu ; Jinling Huang ; Jin Liu ; Li HongSource :
- Cell Death & Disease [ 2041-4889 ] ; 2019.
Abstract
Paeonol (Pae), a phenolic acid compound isolated from the Moutan Cortex, was previously demonstrated to exert multiple anticancer effects. The rational control of autophagy has been considered a potential treatment strategy for epithelial ovarian cancer. However, whether Pae induces autophagy and the relationship between its antitumour activities and autophagy in epithelial ovarian cancer are still unclear. In this study, we found that Pae induced not only antiproliferation activity and apoptosis but also autophagy, and complete autophagic flux was observed in A2780 and SKOV3 cells. In addition, combination treatment with Pae and an autophagy inhibitor (3-methyladenine and hydroxychloroquine) showed significant synergetic effects on inhibiting cell viability and promoting apoptosis in vitro and in the A2780 xenograft model, without severe side effects, which was often had by cisplatin. These results indicate that autophagy induced by Pae has a cytoprotective role in both A2780 and SKOV3 cells. Mechanistically, we found that Pae inhibited the protein kinase B(Akt)/mammalian target of rapamycin (mTOR) pathway. Furthermore, when combined with the inhibitors MK2206 and rapamycin to inhibit Akt and mTOR kinase activity, Pae-induced autophagy was increased. Taken together, our results demonstrate that Pae induced cytoprotective autophagy by inhibiting the Akt/mTOR pathway in ovarian cancer cells. Thus, the strategy of combining Pae with an autophagy inhibitor to block Akt/mTOR-dependent autophagy could enhance the antitumour activity of Pae and warrants further application for the treatment of ovarian cancer.
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DOI: 10.1038/s41419-019-1849-x
PubMed: 31406198
PubMed Central: 6690917
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Paeonol induces cytoprotective autophagy via blocking the Akt/mTOR pathway in ovarian cancer cells</title><author><name sortKey="Gao, Likun" sort="Gao, Likun" uniqKey="Gao L" first="Likun" last="Gao">Likun Gao</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Wang, Zhi" sort="Wang, Zhi" uniqKey="Wang Z" first="Zhi" last="Wang">Zhi Wang</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Lu, Danhua" sort="Lu, Danhua" uniqKey="Lu D" first="Danhua" last="Lu">Danhua Lu</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Huang, Jinling" sort="Huang, Jinling" uniqKey="Huang J" first="Jinling" last="Huang">Jinling Huang</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Liu, Jin" sort="Liu, Jin" uniqKey="Liu J" first="Jin" last="Liu">Jin Liu</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Hong, Li" sort="Hong, Li" uniqKey="Hong L" first="Li" last="Hong">Li Hong</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31406198</idno><idno type="pmc">6690917</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690917</idno><idno type="RBID">PMC:6690917</idno><idno type="doi">10.1038/s41419-019-1849-x</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000068</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000068</idno><idno type="wicri:Area/Pmc/Curation">000068</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000068</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Paeonol induces cytoprotective autophagy via blocking the Akt/mTOR pathway in ovarian cancer cells</title><author><name sortKey="Gao, Likun" sort="Gao, Likun" uniqKey="Gao L" first="Likun" last="Gao">Likun Gao</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Wang, Zhi" sort="Wang, Zhi" uniqKey="Wang Z" first="Zhi" last="Wang">Zhi Wang</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Lu, Danhua" sort="Lu, Danhua" uniqKey="Lu D" first="Danhua" last="Lu">Danhua Lu</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Huang, Jinling" sort="Huang, Jinling" uniqKey="Huang J" first="Jinling" last="Huang">Jinling Huang</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Liu, Jin" sort="Liu, Jin" uniqKey="Liu J" first="Jin" last="Liu">Jin Liu</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author><author><name sortKey="Hong, Li" sort="Hong, Li" uniqKey="Hong L" first="Li" last="Hong">Li Hong</name><affiliation><nlm:aff id="Aff1"></nlm:aff></affiliation></author></analytic><series><title level="j">Cell Death & Disease</title><idno type="eISSN">2041-4889</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="Par1">Paeonol (Pae), a phenolic acid compound isolated from the Moutan Cortex, was previously demonstrated to exert multiple anticancer effects. The rational control of autophagy has been considered a potential treatment strategy for epithelial ovarian cancer. However, whether Pae induces autophagy and the relationship between its antitumour activities and autophagy in epithelial ovarian cancer are still unclear. In this study, we found that Pae induced not only antiproliferation activity and apoptosis but also autophagy, and complete autophagic flux was observed in A2780 and SKOV3 cells. In addition, combination treatment with Pae and an autophagy inhibitor (3-methyladenine and hydroxychloroquine) showed significant synergetic effects on inhibiting cell viability and promoting apoptosis in vitro and in the A2780 xenograft model, without severe side effects, which was often had by cisplatin. These results indicate that autophagy induced by Pae has a cytoprotective role in both A2780 and SKOV3 cells. Mechanistically, we found that Pae inhibited the protein kinase B(Akt)/mammalian target of rapamycin (mTOR) pathway. Furthermore, when combined with the inhibitors MK2206 and rapamycin to inhibit Akt and mTOR kinase activity, Pae-induced autophagy was increased. Taken together, our results demonstrate that Pae induced cytoprotective autophagy by inhibiting the Akt/mTOR pathway in ovarian cancer cells. Thus, the strategy of combining Pae with an autophagy inhibitor to block Akt/mTOR-dependent autophagy could enhance the antitumour activity of Pae and warrants further application for the treatment of ovarian cancer.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Haas, Naomi B" uniqKey="Haas N">Naomi B. Haas</name></author><author><name sortKey="Appleman, Leonard J" uniqKey="Appleman L">Leonard J. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cell Death Dis</journal-id><journal-id journal-id-type="iso-abbrev">Cell Death Dis</journal-id><journal-title-group><journal-title>Cell Death & Disease</journal-title></journal-title-group><issn pub-type="epub">2041-4889</issn><publisher><publisher-name>Nature Publishing Group UK</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31406198</article-id><article-id pub-id-type="pmc">6690917</article-id><article-id pub-id-type="publisher-id">1849</article-id><article-id pub-id-type="doi">10.1038/s41419-019-1849-x</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Paeonol induces cytoprotective autophagy via blocking the Akt/mTOR pathway in ovarian cancer cells</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Gao</surname><given-names>Likun</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Zhi</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Lu</surname><given-names>Danhua</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Jinling</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Jin</given-names></name><xref ref-type="aff" rid="Aff1"></xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Hong</surname><given-names>Li</given-names></name><address><email>drhongli77@163.com</email></address><xref ref-type="aff" rid="Aff1"></xref></contrib><aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1758 2270</institution-id><institution-id institution-id-type="GRID">grid.412632.0</institution-id><institution>Department of Obstetrics and Gynaecology,</institution><institution>Renmin Hospital of Wuhan University,</institution></institution-wrap>Wuhan, People’s Republic of China</aff></contrib-group><pub-date pub-type="epub"><day>13</day><month>8</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>13</day><month>8</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>8</month><year>2019</year></pub-date><volume>10</volume><issue>8</issue><elocation-id>609</elocation-id><history><date date-type="received"><day>5</day><month>4</month><year>2019</year></date><date date-type="rev-recd"><day>21</day><month>7</month><year>2019</year></date><date date-type="accepted"><day>26</day><month>7</month><year>2019</year></date></history><permissions><copyright-statement>© The Author(s) 2019</copyright-statement><license license-type="OpenAccess"><license-p><bold>Open Access</bold> This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>.</license-p></license></permissions><abstract id="Abs1"><p id="Par1">Paeonol (Pae), a phenolic acid compound isolated from the Moutan Cortex, was previously demonstrated to exert multiple anticancer effects. The rational control of autophagy has been considered a potential treatment strategy for epithelial ovarian cancer. However, whether Pae induces autophagy and the relationship between its antitumour activities and autophagy in epithelial ovarian cancer are still unclear. In this study, we found that Pae induced not only antiproliferation activity and apoptosis but also autophagy, and complete autophagic flux was observed in A2780 and SKOV3 cells. In addition, combination treatment with Pae and an autophagy inhibitor (3-methyladenine and hydroxychloroquine) showed significant synergetic effects on inhibiting cell viability and promoting apoptosis in vitro and in the A2780 xenograft model, without severe side effects, which was often had by cisplatin. These results indicate that autophagy induced by Pae has a cytoprotective role in both A2780 and SKOV3 cells. Mechanistically, we found that Pae inhibited the protein kinase B(Akt)/mammalian target of rapamycin (mTOR) pathway. Furthermore, when combined with the inhibitors MK2206 and rapamycin to inhibit Akt and mTOR kinase activity, Pae-induced autophagy was increased. Taken together, our results demonstrate that Pae induced cytoprotective autophagy by inhibiting the Akt/mTOR pathway in ovarian cancer cells. Thus, the strategy of combining Pae with an autophagy inhibitor to block Akt/mTOR-dependent autophagy could enhance the antitumour activity of Pae and warrants further application for the treatment of ovarian cancer.</p></abstract><kwd-group kwd-group-type="npg-subject"><title>Subject terms</title><kwd>Drug development</kwd><kwd>Autophagy</kwd></kwd-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100001809</institution-id><institution>National Natural Science Foundation of China (National Science Foundation of China)</institution></institution-wrap></funding-source><award-id>81771562</award-id><principal-award-recipient><name><surname>Hong</surname><given-names>Li</given-names></name></principal-award-recipient></award-group></funding-group><funding-group><award-group><funding-source><institution-wrap><institution-id institution-id-type="FundRef">https://doi.org/10.13039/501100003819</institution-id><institution>Natural Science Foundation of Hubei Province (Hubei Provincial Natural Science Foundation)</institution></institution-wrap></funding-source><award-id>2010CDB06903</award-id><principal-award-recipient><name><surname>Hong</surname><given-names>Li</given-names></name></principal-award-recipient></award-group></funding-group><custom-meta-group><custom-meta><meta-name>issue-copyright-statement</meta-name><meta-value>© The Author(s) 2019</meta-value></custom-meta></custom-meta-group></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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