Carnosol, a Natural Polyphenol, Inhibits Migration, Metastasis, and Tumor Growth of Breast Cancer via a ROS-Dependent Proteasome Degradation of STAT3
Identifieur interne : 000905 ( Pmc/Checkpoint ); précédent : 000904; suivant : 000906Carnosol, a Natural Polyphenol, Inhibits Migration, Metastasis, and Tumor Growth of Breast Cancer via a ROS-Dependent Proteasome Degradation of STAT3
Auteurs : Halima Alsamri [Émirats arabes unis] ; Hussain El Hasasna [Émirats arabes unis] ; Yusra Al Dhaheri [Émirats arabes unis] ; Ali H. Eid [Liban] ; Samir Attoub [Émirats arabes unis] ; Rabah Iratni [Émirats arabes unis]Source :
- Frontiers in Oncology [ 2234-943X ] ; 2019.
Abstract
We have previously demonstrated that carnosol, a naturally occurring diterpene, inhibited
Url:
DOI: 10.3389/fonc.2019.00743
PubMed: 31456939
PubMed Central: 6698796
Affiliations:
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Carnosol, a Natural Polyphenol, Inhibits Migration, Metastasis, and Tumor Growth of Breast Cancer via a ROS-Dependent Proteasome Degradation of STAT3</title><author><name sortKey="Alsamri, Halima" sort="Alsamri, Halima" uniqKey="Alsamri H" first="Halima" last="Alsamri">Halima Alsamri</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Biology, College of Science, United Arab Emirates University</institution>,<addr-line>Al Ain</addr-line>,<country>United Arab Emirates</country></nlm:aff><country xml:lang="fr">Émirats arabes unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="El Hasasna, Hussain" sort="El Hasasna, Hussain" uniqKey="El Hasasna H" first="Hussain" last="El Hasasna">Hussain El Hasasna</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Biology, College of Science, United Arab Emirates University</institution>,<addr-line>Al Ain</addr-line>,<country>United Arab Emirates</country></nlm:aff><country xml:lang="fr">Émirats arabes unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Al Dhaheri, Yusra" sort="Al Dhaheri, Yusra" uniqKey="Al Dhaheri Y" first="Yusra" last="Al Dhaheri">Yusra Al Dhaheri</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Biology, College of Science, United Arab Emirates University</institution>,<addr-line>Al Ain</addr-line>,<country>United Arab Emirates</country></nlm:aff><country xml:lang="fr">Émirats arabes unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Eid, Ali H" sort="Eid, Ali H" uniqKey="Eid A" first="Ali H." last="Eid">Ali H. Eid</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut</institution>,<addr-line>Beirut</addr-line>,<country>Lebanon</country></nlm:aff><country xml:lang="fr">Liban</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Attoub, Samir" sort="Attoub, Samir" uniqKey="Attoub S" first="Samir" last="Attoub">Samir Attoub</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University</institution>,<addr-line>Al-Ain</addr-line>,<country>United Arab Emirates</country></nlm:aff><country xml:lang="fr">Émirats arabes unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Iratni, Rabah" sort="Iratni, Rabah" uniqKey="Iratni R" first="Rabah" last="Iratni">Rabah Iratni</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Biology, College of Science, United Arab Emirates University</institution>,<addr-line>Al Ain</addr-line>,<country>United Arab Emirates</country></nlm:aff><country xml:lang="fr">Émirats arabes unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31456939</idno><idno type="pmc">6698796</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698796</idno><idno type="RBID">PMC:6698796</idno><idno type="doi">10.3389/fonc.2019.00743</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000562</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000562</idno><idno type="wicri:Area/Pmc/Curation">000562</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000562</idno><idno type="wicri:Area/Pmc/Checkpoint">000905</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000905</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Carnosol, a Natural Polyphenol, Inhibits Migration, Metastasis, and Tumor Growth of Breast Cancer via a ROS-Dependent Proteasome Degradation of STAT3</title><author><name sortKey="Alsamri, Halima" sort="Alsamri, Halima" uniqKey="Alsamri H" first="Halima" last="Alsamri">Halima Alsamri</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Biology, College of Science, United Arab Emirates University</institution>,<addr-line>Al Ain</addr-line>,<country>United Arab Emirates</country></nlm:aff><country xml:lang="fr">Émirats arabes unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="El Hasasna, Hussain" sort="El Hasasna, Hussain" uniqKey="El Hasasna H" first="Hussain" last="El Hasasna">Hussain El Hasasna</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Biology, College of Science, United Arab Emirates University</institution>,<addr-line>Al Ain</addr-line>,<country>United Arab Emirates</country></nlm:aff><country xml:lang="fr">Émirats arabes unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Al Dhaheri, Yusra" sort="Al Dhaheri, Yusra" uniqKey="Al Dhaheri Y" first="Yusra" last="Al Dhaheri">Yusra Al Dhaheri</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Biology, College of Science, United Arab Emirates University</institution>,<addr-line>Al Ain</addr-line>,<country>United Arab Emirates</country></nlm:aff><country xml:lang="fr">Émirats arabes unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Eid, Ali H" sort="Eid, Ali H" uniqKey="Eid A" first="Ali H." last="Eid">Ali H. Eid</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut</institution>,<addr-line>Beirut</addr-line>,<country>Lebanon</country></nlm:aff><country xml:lang="fr">Liban</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Attoub, Samir" sort="Attoub, Samir" uniqKey="Attoub S" first="Samir" last="Attoub">Samir Attoub</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University</institution>,<addr-line>Al-Ain</addr-line>,<country>United Arab Emirates</country></nlm:aff><country xml:lang="fr">Émirats arabes unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Iratni, Rabah" sort="Iratni, Rabah" uniqKey="Iratni R" first="Rabah" last="Iratni">Rabah Iratni</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Department of Biology, College of Science, United Arab Emirates University</institution>,<addr-line>Al Ain</addr-line>,<country>United Arab Emirates</country></nlm:aff><country xml:lang="fr">Émirats arabes unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Frontiers in Oncology</title><idno type="eISSN">2234-943X</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>We have previously demonstrated that carnosol, a naturally occurring diterpene, inhibited <italic>in vitro</italic> cell viability and colony growth, as well as induced cell cycle arrest, autophagy and apoptosis in human triple negative breast cancer (TNBC) cells. In the present study, we evaluated the ability of carnosol to inhibit tumor growth and metastasis <italic>in vivo</italic>. We found that non-cytotoxic concentrations of carnosol inhibited the migration and invasion of MDA-MB-231 cells in wound healing and matrigel invasion assays. Furthermore, gelatin zymography, ELISA, and RT-PCR assays revealed that carnosol inhibited the activity and downregulation the expression of MMP-9. Mechanistically, we demonstrated that carnosol suppressed the activation of STAT3 signaling pathway through a ROS-dependent targeting of STAT3 to proteasome-degradation in breast cancer cells (MDA-MB-231, Hs578T, MCF-7, and T47D). We show that blockade of proteasome activity, by MG-132 and bortezomib, or ROS accumulation, by N-acetylcysteine (NAC), restored the level of STAT3 protein. In addition, using chick embryo tumor growth assay, we showed that carnosol significantly and markedly suppressed tumor growth and metastasis of breast cancer xenografts. To the best of our knowledge, this is the first report which shows that carnosol specifically targets signal transducer and activator of transcription 3 (STAT3) for proteasome degradation in breast cancer. Our study further provide evidence that carnosol may represent a promising therapeutic candidate that canmodulate breast cancer growth and metastasis.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Cancer Ey, Facts" uniqKey="Cancer Ey F">Facts Cancer–Key</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yersal, O" uniqKey="Yersal O">O Yersal</name></author><author><name sortKey="Barutca, S" uniqKey="Barutca S">S Barutca</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kreike, B" uniqKey="Kreike B">B Kreike</name></author><author><name sortKey="Van Kouwenhove, M" uniqKey="Van Kouwenhove M">M van Kouwenhove</name></author><author><name sortKey="Horlings, H" uniqKey="Horlings H">H Horlings</name></author><author><name sortKey="Weigelt, B" uniqKey="Weigelt B">B Weigelt</name></author><author><name sortKey="Peterse, H" uniqKey="Peterse H">H 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Front Oncol</journal-id><journal-id journal-id-type="iso-abbrev">Front Oncol</journal-id><journal-id journal-id-type="publisher-id">Front. Oncol.</journal-id><journal-title-group><journal-title>Frontiers in Oncology</journal-title></journal-title-group><issn pub-type="epub">2234-943X</issn><publisher><publisher-name>Frontiers Media S.A.</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31456939</article-id><article-id pub-id-type="pmc">6698796</article-id><article-id pub-id-type="doi">10.3389/fonc.2019.00743</article-id><article-categories><subj-group subj-group-type="heading"><subject>Oncology</subject><subj-group><subject>Original Research</subject></subj-group></subj-group></article-categories><title-group><article-title>Carnosol, a Natural Polyphenol, Inhibits Migration, Metastasis, and Tumor Growth of Breast Cancer via a ROS-Dependent Proteasome Degradation of STAT3</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Alsamri</surname><given-names>Halima</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/762154/overview"></uri></contrib><contrib contrib-type="author"><name><surname>El Hasasna</surname><given-names>Hussain</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="author-notes" rid="fn002"><sup>†</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/750951/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Al Dhaheri</surname><given-names>Yusra</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/761890/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Eid</surname><given-names>Ali H.</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/179741/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Attoub</surname><given-names>Samir</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/49444/overview"></uri></contrib><contrib contrib-type="author"><name><surname>Iratni</surname><given-names>Rabah</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="c001"><sup>*</sup></xref><uri xlink:type="simple" xlink:href="http://loop.frontiersin.org/people/550382/overview"></uri></contrib></contrib-group><aff id="aff1"><sup>1</sup><institution>Department of Biology, College of Science, United Arab Emirates University</institution>,<addr-line>Al Ain</addr-line>,<country>United Arab Emirates</country></aff><aff id="aff2"><sup>2</sup><institution>Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut</institution>,<addr-line>Beirut</addr-line>,<country>Lebanon</country></aff><aff id="aff3"><sup>3</sup><institution>Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University</institution>,<addr-line>Al-Ain</addr-line>,<country>United Arab Emirates</country></aff><author-notes><fn fn-type="edited-by"><p>Edited by: Zhi Sheng, Virginia Tech, United States</p></fn><fn fn-type="edited-by"><p>Reviewed by: Keqiang Zhang, City of Hope National Medical Center, United States; Qingping Dou, Wayne State University, United States</p></fn><corresp id="c001">*Correspondence: Rabah Iratni <email>R_iratni@uaeu.ac.ae</email></corresp><fn fn-type="other" id="fn001"><p>This article was submitted to Cancer Molecular Targets and Therapeutics, a section of the journal Frontiers in Oncology</p></fn><fn fn-type="present-address" id="fn002"><p>†Present Address: Hussain El Hasasna, Cancer Cluster, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada</p></fn></author-notes><pub-date pub-type="epub"><day>08</day><month>8</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>9</volume><elocation-id>743</elocation-id><history><date date-type="received"><day>03</day><month>6</month><year>2019</year></date><date date-type="accepted"><day>23</day><month>7</month><year>2019</year></date></history><permissions><copyright-statement>Copyright © 2019 Alsamri, El Hasasna, Al Dhaheri, Eid, Attoub and Iratni.</copyright-statement><copyright-year>2019</copyright-year><copyright-holder>Alsamri, El Hasasna, Al Dhaheri, Eid, Attoub and Iratni</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>We have previously demonstrated that carnosol, a naturally occurring diterpene, inhibited <italic>in vitro</italic> cell viability and colony growth, as well as induced cell cycle arrest, autophagy and apoptosis in human triple negative breast cancer (TNBC) cells. In the present study, we evaluated the ability of carnosol to inhibit tumor growth and metastasis <italic>in vivo</italic>. We found that non-cytotoxic concentrations of carnosol inhibited the migration and invasion of MDA-MB-231 cells in wound healing and matrigel invasion assays. Furthermore, gelatin zymography, ELISA, and RT-PCR assays revealed that carnosol inhibited the activity and downregulation the expression of MMP-9. Mechanistically, we demonstrated that carnosol suppressed the activation of STAT3 signaling pathway through a ROS-dependent targeting of STAT3 to proteasome-degradation in breast cancer cells (MDA-MB-231, Hs578T, MCF-7, and T47D). We show that blockade of proteasome activity, by MG-132 and bortezomib, or ROS accumulation, by N-acetylcysteine (NAC), restored the level of STAT3 protein. In addition, using chick embryo tumor growth assay, we showed that carnosol significantly and markedly suppressed tumor growth and metastasis of breast cancer xenografts. To the best of our knowledge, this is the first report which shows that carnosol specifically targets signal transducer and activator of transcription 3 (STAT3) for proteasome degradation in breast cancer. Our study further provide evidence that carnosol may represent a promising therapeutic candidate that canmodulate breast cancer growth and metastasis.</p></abstract><kwd-group><kwd>triple negative breast cancer (TNBC)</kwd><kwd>stat3</kwd><kwd>reactive oxygen species</kwd><kwd>proteasome</kwd><kwd>tumor growth</kwd><kwd>metastasis</kwd></kwd-group><funding-group><award-group><funding-source id="cn001">Al Jalila Foundation<named-content content-type="fundref-id">10.13039/100012001</named-content></funding-source></award-group><award-group><funding-source id="cn002">United Arab Emirates University<named-content content-type="fundref-id">10.13039/501100006013</named-content></funding-source></award-group></funding-group><counts><fig-count count="8"></fig-count><table-count count="0"></table-count><equation-count count="0"></equation-count><ref-count count="52"></ref-count><page-count count="11"></page-count><word-count count="7627"></word-count></counts></article-meta></front></pmc><affiliations><list><country><li>Liban</li><li>Émirats arabes unis</li></country></list><tree><country name="Émirats arabes unis"><noRegion><name sortKey="Alsamri, Halima" sort="Alsamri, Halima" uniqKey="Alsamri H" first="Halima" last="Alsamri">Halima Alsamri</name></noRegion><name sortKey="Al Dhaheri, Yusra" sort="Al Dhaheri, Yusra" uniqKey="Al Dhaheri Y" first="Yusra" last="Al Dhaheri">Yusra Al Dhaheri</name><name sortKey="Attoub, Samir" sort="Attoub, Samir" uniqKey="Attoub S" first="Samir" last="Attoub">Samir Attoub</name><name sortKey="El Hasasna, Hussain" sort="El Hasasna, Hussain" uniqKey="El Hasasna H" first="Hussain" last="El Hasasna">Hussain El Hasasna</name><name sortKey="Iratni, Rabah" sort="Iratni, Rabah" uniqKey="Iratni R" first="Rabah" last="Iratni">Rabah Iratni</name></country><country name="Liban"><noRegion><name sortKey="Eid, Ali H" sort="Eid, Ali H" uniqKey="Eid A" first="Ali H." last="Eid">Ali H. 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