Methyloleanolate Induces Apoptotic And Autophagic Cell Death Via Reactive Oxygen Species Generation And c-Jun N-terminal Kinase Phosphorylation
Identifieur interne : 000739 ( Pmc/Curation ); précédent : 000738; suivant : 000740Methyloleanolate Induces Apoptotic And Autophagic Cell Death Via Reactive Oxygen Species Generation And c-Jun N-terminal Kinase Phosphorylation
Auteurs : Myoung Seok Jeong [Corée du Sud] ; Ji Hoon Jung [Corée du Sud] ; Hyemin Lee [Corée du Sud] ; Chang Geun Kim [Corée du Sud] ; Sung-Hoon Kim [Corée du Sud]Source :
- OncoTargets and therapy [ 1178-6930 ] ; 2019.
Abstract
To develop a potent anticancer agent similar to oleanolate, the underlying mechanisms of its derivative, methyloleanolate, in the apoptosis and autophagy of A549 and H1299 cells were elucidated.
The aim of the present study was to investigate the effect of methyloleanolate in inducing apoptotic and autophagic cell death in cancer cells.
Flow cytometric analysis with Annexin V/PI staining, Western blot analysis, and immunofluorescence analysis were conducted in A549 and H1299 cells.
Methyloleanolate increased the fraction of Annexin V/PI apoptotic cells and activated caspase-8, caspase-3, and death receptor 5 (DR5) more than oleanolate in A549 and H1299 cells pretreated with pancaspase inhibitor z-VAD-fmk and DR5 depletion. Also, methyloleanolate induced autophagic features of microtubule-associated protein light chain 3 3BII (LC3BII) conversion and puncta in A549 and H1299 cells, along with autophagosomes and vacuoles. Methyloleanolate blocked autophagy flux for impaired autophagy and chloroquine (CQ)-enhanced microtubule-associated protein LC3BII accumulation and cytotoxicity in A549 and H1299 cells, although 3-methyladenine (3-MA) did not. Interestingly, LC3BII accumulation was detected only in methyloleanolate-treated autophagy-related gene 5 (
Overall, the findings suggest that methyloleanolate induces apoptotic and autophagic cell death in non–small cell lung cancers via reactive oxygen species generation and c-Jun N-terminal kinase phosphorylation.
Url:
DOI: 10.2147/OTT.S211904
PubMed: 31695422
PubMed Central: 6815788
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University</institution>,<addr-line>Dongdaemun-Gu</addr-line>,<addr-line>Seoul</addr-line><addr-line>02447</addr-line>,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Jung, Ji Hoon" sort="Jung, Ji Hoon" uniqKey="Jung J" first="Ji Hoon" last="Jung">Ji Hoon Jung</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>College of Korean Medicine, Kyung Hee University</institution>,<addr-line>Dongdaemun-Gu</addr-line>,<addr-line>Seoul</addr-line><addr-line>02447</addr-line>,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Lee, Hyemin" sort="Lee, Hyemin" uniqKey="Lee H" first="Hyemin" last="Lee">Hyemin Lee</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>College of Korean Medicine, Kyung Hee University</institution>,<addr-line>Dongdaemun-Gu</addr-line>,<addr-line>Seoul</addr-line><addr-line>02447</addr-line>,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Chang Geun" sort="Kim, Chang Geun" uniqKey="Kim C" first="Chang Geun" last="Kim">Chang Geun Kim</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>College of Korean Medicine, Kyung Hee University</institution>,<addr-line>Dongdaemun-Gu</addr-line>,<addr-line>Seoul</addr-line><addr-line>02447</addr-line>,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, Sung Hoon" sort="Kim, Sung Hoon" uniqKey="Kim S" first="Sung-Hoon" last="Kim">Sung-Hoon Kim</name><affiliation wicri:level="1"><nlm:aff id="AFF0001"><institution>College of Korean Medicine, Kyung Hee University</institution>,<addr-line>Dongdaemun-Gu</addr-line>,<addr-line>Seoul</addr-line><addr-line>02447</addr-line>,<country>Republic of Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">OncoTargets and therapy</title><idno type="eISSN">1178-6930</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec id="S2001"><title>Background</title><p>To develop a potent anticancer agent similar to oleanolate, the underlying mechanisms of its derivative, methyloleanolate, in the apoptosis and autophagy of A549 and H1299 cells were elucidated.</p></sec><sec id="S2002"><title>Purpose</title><p>The aim of the present study was to investigate the effect of methyloleanolate in inducing apoptotic and autophagic cell death in cancer cells.</p></sec><sec id="S2003"><title>Materials and methods</title><p>Flow cytometric analysis with Annexin V/PI staining, Western blot analysis, and immunofluorescence analysis were conducted in A549 and H1299 cells.</p></sec><sec id="S2004"><title>Results</title><p>Methyloleanolate increased the fraction of Annexin V/PI apoptotic cells and activated caspase-8, caspase-3, and death receptor 5 (DR5) more than oleanolate in A549 and H1299 cells pretreated with pancaspase inhibitor z-VAD-fmk and DR5 depletion. Also, methyloleanolate induced autophagic features of microtubule-associated protein light chain 3 3BII (LC3BII) conversion and puncta in A549 and H1299 cells, along with autophagosomes and vacuoles. Methyloleanolate blocked autophagy flux for impaired autophagy and chloroquine (CQ)-enhanced microtubule-associated protein LC3BII accumulation and cytotoxicity in A549 and H1299 cells, although 3-methyladenine (3-MA) did not. Interestingly, LC3BII accumulation was detected only in methyloleanolate-treated autophagy-related gene 5 (<italic>ATG5</italic>)<sup>+/+</sup> mouse embryonic fibroblast (MEF) cells but not in <italic>ATG5</italic><sup>−/-</sup> MEF cells. Methyloleanolate reduced p-mTOR but activated p-c-Jun N-terminal kinases and reactive oxygen species production in A549 and H1299 cells. Conversely, <sc>n</sc>-acetyl-<sc>l</sc>-cysteine and SP600125 blocked apoptotic and autophagic cascades caused by methyloleanolate in A549 and H1299 cells.</p></sec><sec id="S2005"><title>Conclusion</title><p>Overall, the findings suggest that methyloleanolate induces apoptotic and autophagic cell death in non–small cell lung cancers via reactive oxygen species generation and c-Jun N-terminal kinase phosphorylation.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Onco Targets Ther</journal-id><journal-id journal-id-type="iso-abbrev">Onco Targets Ther</journal-id><journal-id journal-id-type="publisher-id">OTT</journal-id><journal-id journal-id-type="pmc">ott</journal-id><journal-title-group><journal-title>OncoTargets and therapy</journal-title></journal-title-group><issn pub-type="epub">1178-6930</issn><publisher><publisher-name>Dove</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31695422</article-id><article-id pub-id-type="pmc">6815788</article-id><article-id pub-id-type="publisher-id">211904</article-id><article-id pub-id-type="doi">10.2147/OTT.S211904</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Research</subject></subj-group></article-categories><title-group><article-title>Methyloleanolate Induces Apoptotic And Autophagic Cell Death Via Reactive Oxygen Species Generation And c-Jun N-terminal Kinase Phosphorylation</article-title><alt-title alt-title-type="running-authors">Jeong et al</alt-title><alt-title alt-title-type="running-title">Jeong et al</alt-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Jeong</surname><given-names>Myoung Seok</given-names></name><xref ref-type="aff" rid="AFF0001">1</xref><xref ref-type="author-notes" rid="FT0001"></xref></contrib><contrib contrib-type="author" equal-contrib="yes"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0002-5644-5960</contrib-id><name><surname>Jung</surname><given-names>Ji Hoon</given-names></name><xref ref-type="aff" rid="AFF0001">1</xref><xref ref-type="author-notes" rid="FT0001"></xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0003-3910-5611</contrib-id><name><surname>Lee</surname><given-names>Hyemin</given-names></name><xref ref-type="aff" rid="AFF0001">1</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Chang Geun</given-names></name><xref ref-type="aff" rid="AFF0001">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="false">http://orcid.org/0000-0003-2423-1973</contrib-id><name><surname>Kim</surname><given-names>Sung-Hoon</given-names></name><xref ref-type="corresp" rid="AN0001"></xref><xref ref-type="aff" rid="AFF0001">1</xref></contrib><aff id="AFF0001"><label>1</label><institution>College of Korean Medicine, Kyung Hee University</institution>,<addr-line>Dongdaemun-Gu</addr-line>,<addr-line>Seoul</addr-line><addr-line>02447</addr-line>,<country>Republic of Korea</country></aff></contrib-group><author-notes><corresp id="AN0001">Correspondence: Sung-Hoon Kim <institution>College of Korean Medicine, Kyung Hee University</institution>, <addr-line>26, Kyungheedae-ro</addr-line>, <addr-line>Dongdaemun-gu</addr-line>, <addr-line>Seoul</addr-line><addr-line>02447</addr-line>, <country>Republic of Korea</country><phone>Tel +82-2-961-9233</phone><fax>Fax +82-2-961-9598</fax> Email sungkim7@khu.ac.kr</corresp><fn id="FT0001"><label>*</label><p>These authors contributed equally to this work</p></fn></author-notes><pub-date pub-type="epub"><day>23</day><month>10</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>12</volume><fpage>8621</fpage><lpage>8635</lpage><history><date date-type="received"><day>11</day><month>4</month><year>2019</year></date><date date-type="accepted"><day>01</day><month>9</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 Jeong et al.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Jeong et al.</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/"><license-p>This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at <ext-link ext-link-type="uri" xlink:href="https://www.dovepress.com/terms.php">https://www.dovepress.com/terms.php</ext-link> and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc/3.0/">http://creativecommons.org/licenses/by-nc/3.0/</ext-link>). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (<ext-link ext-link-type="uri" xlink:href="https://www.dovepress.com/terms.php">https://www.dovepress.com/terms.php</ext-link>).</license-p></license></permissions><abstract><sec id="S2001"><title>Background</title><p>To develop a potent anticancer agent similar to oleanolate, the underlying mechanisms of its derivative, methyloleanolate, in the apoptosis and autophagy of A549 and H1299 cells were elucidated.</p></sec><sec id="S2002"><title>Purpose</title><p>The aim of the present study was to investigate the effect of methyloleanolate in inducing apoptotic and autophagic cell death in cancer cells.</p></sec><sec id="S2003"><title>Materials and methods</title><p>Flow cytometric analysis with Annexin V/PI staining, Western blot analysis, and immunofluorescence analysis were conducted in A549 and H1299 cells.</p></sec><sec id="S2004"><title>Results</title><p>Methyloleanolate increased the fraction of Annexin V/PI apoptotic cells and activated caspase-8, caspase-3, and death receptor 5 (DR5) more than oleanolate in A549 and H1299 cells pretreated with pancaspase inhibitor z-VAD-fmk and DR5 depletion. Also, methyloleanolate induced autophagic features of microtubule-associated protein light chain 3 3BII (LC3BII) conversion and puncta in A549 and H1299 cells, along with autophagosomes and vacuoles. Methyloleanolate blocked autophagy flux for impaired autophagy and chloroquine (CQ)-enhanced microtubule-associated protein LC3BII accumulation and cytotoxicity in A549 and H1299 cells, although 3-methyladenine (3-MA) did not. Interestingly, LC3BII accumulation was detected only in methyloleanolate-treated autophagy-related gene 5 (<italic>ATG5</italic>)<sup>+/+</sup> mouse embryonic fibroblast (MEF) cells but not in <italic>ATG5</italic><sup>−/-</sup> MEF cells. Methyloleanolate reduced p-mTOR but activated p-c-Jun N-terminal kinases and reactive oxygen species production in A549 and H1299 cells. Conversely, <sc>n</sc>-acetyl-<sc>l</sc>-cysteine and SP600125 blocked apoptotic and autophagic cascades caused by methyloleanolate in A549 and H1299 cells.</p></sec><sec id="S2005"><title>Conclusion</title><p>Overall, the findings suggest that methyloleanolate induces apoptotic and autophagic cell death in non–small cell lung cancers via reactive oxygen species generation and c-Jun N-terminal kinase phosphorylation.</p></sec></abstract><kwd-group kwd-group-type="author"><title>Keywords</title><kwd>methyloleanolate</kwd><kwd>apoptosis</kwd><kwd>autophagy</kwd><kwd>JNK</kwd><kwd>ROS</kwd></kwd-group><counts><fig-count count="7"></fig-count><ref-count count="50"></ref-count><page-count count="15"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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