Pterostilbene, An Active Constituent of Blueberries, Suppresses Proliferation Potential of Human Cholangiocarcinoma via Enhancing the Autophagic Flux
Identifieur interne : 000573 ( Pmc/Curation ); précédent : 000572; suivant : 000574Pterostilbene, An Active Constituent of Blueberries, Suppresses Proliferation Potential of Human Cholangiocarcinoma via Enhancing the Autophagic Flux
Auteurs : Dong Wang [République populaire de Chine] ; Haoran Guo [République populaire de Chine] ; Huahong Yang [République populaire de Chine] ; Dongyin Wang [République populaire de Chine] ; Pujun Gao [République populaire de Chine] ; Wei Wei [République populaire de Chine]Source :
- Frontiers in Pharmacology [ 1663-9812 ] ; 2019.
Abstract
Url:
DOI: 10.3389/fphar.2019.01238
PubMed: 31695612
PubMed Central: 6817474
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Pterostilbene, An Active Constituent of Blueberries, Suppresses Proliferation Potential of Human Cholangiocarcinoma <italic>via</italic> Enhancing the Autophagic Flux</title><author><name sortKey="Wang, Dong" sort="Wang, Dong" uniqKey="Wang D" first="Dong" last="Wang">Dong Wang</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Hepatology, The First Hospital of Jilin University, Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Virology and AIDS Research, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Guo, Haoran" sort="Guo, Haoran" uniqKey="Guo H" first="Haoran" last="Guo">Haoran Guo</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Virology and AIDS Research, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yang, Huahong" sort="Yang, Huahong" uniqKey="Yang H" first="Huahong" last="Yang">Huahong Yang</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Respiration, The First Hospital of Jilin University, Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Dongyin" sort="Wang, Dongyin" uniqKey="Wang D" first="Dongyin" last="Wang">Dongyin Wang</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Hepatology, The First Hospital of Jilin University, Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gao, Pujun" sort="Gao, Pujun" uniqKey="Gao P" first="Pujun" last="Gao">Pujun Gao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Hepatology, The First Hospital of Jilin University, Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wei, Wei" sort="Wei, Wei" uniqKey="Wei W" first="Wei" last="Wei">Wei Wei</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Virology and AIDS Research, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31695612</idno><idno type="pmc">6817474</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817474</idno><idno type="RBID">PMC:6817474</idno><idno type="doi">10.3389/fphar.2019.01238</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000573</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000573</idno><idno type="wicri:Area/Pmc/Curation">000573</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000573</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Pterostilbene, An Active Constituent of Blueberries, Suppresses Proliferation Potential of Human Cholangiocarcinoma <italic>via</italic> Enhancing the Autophagic Flux</title><author><name sortKey="Wang, Dong" sort="Wang, Dong" uniqKey="Wang D" first="Dong" last="Wang">Dong Wang</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Hepatology, The First Hospital of Jilin University, Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Virology and AIDS Research, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Guo, Haoran" sort="Guo, Haoran" uniqKey="Guo H" first="Haoran" last="Guo">Haoran Guo</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Virology and AIDS Research, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Yang, Huahong" sort="Yang, Huahong" uniqKey="Yang H" first="Huahong" last="Yang">Huahong Yang</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Respiration, The First Hospital of Jilin University, Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Dongyin" sort="Wang, Dongyin" uniqKey="Wang D" first="Dongyin" last="Wang">Dongyin Wang</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Hepatology, The First Hospital of Jilin University, Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Gao, Pujun" sort="Gao, Pujun" uniqKey="Gao P" first="Pujun" last="Gao">Pujun Gao</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Hepatology, The First Hospital of Jilin University, Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Wei, Wei" sort="Wei, Wei" uniqKey="Wei W" first="Wei" last="Wei">Wei Wei</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Institute of Virology and AIDS Research, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Frontiers in Pharmacology</title><idno type="eISSN">1663-9812</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><bold>Background:</bold> Human cholangiocarcinoma (CCA) is a highly lethal cancer that occurs in the biliary tract. It is characterized by early invasion, poor outcomes, and resistance to current chemotherapies. To date, an effective therapeutic strategy for this devastating and deadly disease is lacking. Pterostilbene, a natural compound found in the extracts of many plants including blueberries, kino tree, or dragon blood tree, has several health benefits. However, its effects on CCA have not been clarified. Here, we investigated the potential application of pterostilbene for the treatment of human CCA <italic>in vitro</italic> and <italic>in vivo</italic>.</p><p><bold>Methods:</bold> The effects of pterostilbene on CCA cells were determined by assessing cell viability (CCK), cell proliferation, and colony formation. Cell cycle arrest and apoptosis were measured by flow cytometric analysis, whereas proteins related to autophagy were detected by immunofluorescence and immunoblotting assays. A well-established xenograft mouse model was used to evaluate the effects of pterostilbene on tumor growth <italic>in vivo</italic>.</p><p><bold>Results:</bold> Pterostilbene induced dose-dependent and time-dependent cytotoxic effects, inhibited proliferation and colony formation, and caused S phase cell cycle arrest in CCA cells. Instead of triggering apoptotic cell death in these cells, pterostilbene was found to exert potent autophagy-inducing effects, and this correlated with p62 downregulation, elevated expression of endogenous Beclin-1, ATG5, and LC3-II, and increases in LC3 puncta. Pretreating cancer cells with the autophagy inhibitor 3-MA suppressed the induction of autophagy and antitumor activity caused by pterostilbene. Finally, we confirmed that pterostilbene inhibited tumor growth in a CCA xenograft mouse model with minimal general toxicity.</p><p><bold>Conclusion:</bold> Taken together, our findings indicate that pterostilbene, through the induction of autophagic flux, acts as an anti-cancer agent against CCA cells.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Banales, J M" uniqKey="Banales J">J. M. Banales</name></author><author><name sortKey="Cardinale, V" uniqKey="Cardinale V">V. Cardinale</name></author><author><name sortKey="Carpino, G" uniqKey="Carpino G">G. Carpino</name></author><author><name sortKey="Marzioni, M" uniqKey="Marzioni M">M. Marzioni</name></author><author><name sortKey="Andersen, J B" uniqKey="Andersen J">J. B. Andersen</name></author><author><name sortKey="Invernizzi, P" uniqKey="Invernizzi P">P. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Front Pharmacol</journal-id><journal-id journal-id-type="iso-abbrev">Front Pharmacol</journal-id><journal-id journal-id-type="publisher-id">Front. Pharmacol.</journal-id><journal-title-group><journal-title>Frontiers in Pharmacology</journal-title></journal-title-group><issn pub-type="epub">1663-9812</issn><publisher><publisher-name>Frontiers Media S.A.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31695612</article-id><article-id pub-id-type="pmc">6817474</article-id><article-id pub-id-type="doi">10.3389/fphar.2019.01238</article-id><article-categories><subj-group subj-group-type="heading"><subject>Pharmacology</subject><subj-group><subject>Original Research</subject></subj-group></subj-group></article-categories><title-group><article-title>Pterostilbene, An Active Constituent of Blueberries, Suppresses Proliferation Potential of Human Cholangiocarcinoma <italic>via</italic> Enhancing the Autophagic Flux</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Dong</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Guo</surname><given-names>Haoran</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Huahong</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Dongyin</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gao</surname><given-names>Pujun</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="author-notes" rid="fn001"><sup>*</sup></xref><uri xlink:type="simple" xlink:href="https://loop.frontiersin.org/people/758279"></uri></contrib><contrib contrib-type="author"><name><surname>Wei</surname><given-names>Wei</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="author-notes" rid="fn001"><sup>*</sup></xref><uri xlink:type="simple" xlink:href="https://loop.frontiersin.org/people/584381"></uri></contrib></contrib-group><aff id="aff1"><sup>1</sup><institution>Department of Hepatology, The First Hospital of Jilin University, Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></aff><aff id="aff2"><sup>2</sup><institution>Institute of Virology and AIDS Research, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></aff><aff id="aff3"><sup>3</sup><institution>Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, Institute of Translational Medicine, The First Hospital of Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></aff><aff id="aff4"><sup>4</sup><institution>Department of Respiration, The First Hospital of Jilin University, Jilin University</institution>,<addr-line>Changchun</addr-line>,<country>China</country></aff><author-notes><fn fn-type="edited-by"><p>Edited by: Letizia Polito, University of Bologna, Italy</p></fn><fn fn-type="edited-by"><p>Reviewed by: Sujit Kumar Bhutia, National Institute of Technology Rourkela, India; Krishna Beer Singh, University of Pittsburgh, United States</p></fn><corresp id="fn001">*Correspondence: Pujun Gao, <email xlink:href="mailto:gpj0411@163.com" xlink:type="simple">gpj0411@163.com</email>; Wei Wei, <email xlink:href="mailto:wwei6@jlu.edu.cn" xlink:type="simple">wwei6@jlu.edu.cn</email></corresp><fn fn-type="other" id="fn002"><p>This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology</p></fn></author-notes><pub-date pub-type="epub"><day>22</day><month>10</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>10</volume><elocation-id>1238</elocation-id><history><date date-type="received"><day>23</day><month>6</month><year>2019</year></date><date date-type="accepted"><day>27</day><month>9</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2019 Wang, Guo, Yang, Wang, Gao and Wei</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Wang, Guo, Yang, Wang, Gao and Wei</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.</license-p></license></permissions><abstract><p><bold>Background:</bold> Human cholangiocarcinoma (CCA) is a highly lethal cancer that occurs in the biliary tract. It is characterized by early invasion, poor outcomes, and resistance to current chemotherapies. To date, an effective therapeutic strategy for this devastating and deadly disease is lacking. Pterostilbene, a natural compound found in the extracts of many plants including blueberries, kino tree, or dragon blood tree, has several health benefits. However, its effects on CCA have not been clarified. Here, we investigated the potential application of pterostilbene for the treatment of human CCA <italic>in vitro</italic> and <italic>in vivo</italic>.</p><p><bold>Methods:</bold> The effects of pterostilbene on CCA cells were determined by assessing cell viability (CCK), cell proliferation, and colony formation. Cell cycle arrest and apoptosis were measured by flow cytometric analysis, whereas proteins related to autophagy were detected by immunofluorescence and immunoblotting assays. A well-established xenograft mouse model was used to evaluate the effects of pterostilbene on tumor growth <italic>in vivo</italic>.</p><p><bold>Results:</bold> Pterostilbene induced dose-dependent and time-dependent cytotoxic effects, inhibited proliferation and colony formation, and caused S phase cell cycle arrest in CCA cells. Instead of triggering apoptotic cell death in these cells, pterostilbene was found to exert potent autophagy-inducing effects, and this correlated with p62 downregulation, elevated expression of endogenous Beclin-1, ATG5, and LC3-II, and increases in LC3 puncta. Pretreating cancer cells with the autophagy inhibitor 3-MA suppressed the induction of autophagy and antitumor activity caused by pterostilbene. Finally, we confirmed that pterostilbene inhibited tumor growth in a CCA xenograft mouse model with minimal general toxicity.</p><p><bold>Conclusion:</bold> Taken together, our findings indicate that pterostilbene, through the induction of autophagic flux, acts as an anti-cancer agent against CCA cells.</p></abstract><kwd-group><kwd>pterostilbene</kwd><kwd>human cholangiocarcinoma</kwd><kwd>autophagy</kwd><kwd>anti-cancer</kwd><kwd>light chain 3</kwd></kwd-group><counts><fig-count count="5"></fig-count><table-count count="0"></table-count><equation-count count="0"></equation-count><ref-count count="31"></ref-count><page-count count="11"></page-count><word-count count="4707"></word-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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