ROS-mediated activation and mitochondrial translocation of CaMKII contributes to Drp1-dependent mitochondrial fission and apoptosis in triple-negative breast cancer cells by isorhamnetin and chloroquine
Identifieur interne : 000105 ( Pmc/Curation ); précédent : 000104; suivant : 000106ROS-mediated activation and mitochondrial translocation of CaMKII contributes to Drp1-dependent mitochondrial fission and apoptosis in triple-negative breast cancer cells by isorhamnetin and chloroquine
Auteurs : Jinjiao Hu [République populaire de Chine] ; Yanhao Zhang [République populaire de Chine] ; Xiuxing Jiang [République populaire de Chine] ; Hongwei Zhang [République populaire de Chine] ; Ziyi Gao [États-Unis] ; Yunong Li [République populaire de Chine] ; Ruoqiu Fu [République populaire de Chine] ; Lirong Li [République populaire de Chine] ; Jie Li [République populaire de Chine] ; Hongjuan Cui [République populaire de Chine] ; Ning Gao [République populaire de Chine]Source :
- Journal of Experimental & Clinical Cancer Research : CR [ 0392-9078 ] ; 2019.
Abstract
Triple-negative breast cancer (TNBC) is often aggressive and associated with a poor prognosis. Due to the lack of available targeted therapies and to problems of resistance with conventional chemotherapeutic agents, finding new treatments for TNBC remains a challenge and a better therapeutic strategy is urgently required.
TNBC cells and xenograft mice were treated with a combination of chloroquine (CQ) and isorhamnetin (IH). Mitochondrial fission, apoptosis, and related signaling pathways were determined by flow cytometry, immunofluorescence, and related molecular biological techniques.
The inhibition of autophagy/mitophagy by CQ selectively enhances IH-induced mitochondrial fission and apoptosis in TNBC cells but not in estrogen-dependent breast cancer cells. These events were accompanied by mitochondrial translocation of Bax and the release of cytochrome c. Mechanistically, these effects were associated with oxidative stress-mediated phosphorylation of CaMKII (Thr286) and Drp1 (S616), and subsequent mitochondrial translocation of CaMKII and Drp1. The interruption of the CaMKII pathway by genetic approaches (e.g. CaMKII mutant or siRNA) attenuated combination-mediated mitochondrial fission and apoptosis. The combination of CQ/IH was a marked inhibitor tumor growth, inducing apoptosis in the TNBC xenograft mouse model in association with the activation of CaMKII and Drp1 (S616).
Our study highlights the critical role of ROS-mediating CaMKII/Drp1 signaling in the regulation of mitochondrial fission and apoptosis induced by combination of CQ/IH. These findings also suggest that IH could potentially be further developed as a novel chemotherapeutic agent. Furthermore, a combination of IH with classic autophagy/mitophagy inhibitor could represent a novel therapeutic strategy for the treatment of TNBC.
The online version of this article (10.1186/s13046-019-1201-4) contains supplementary material, which is available to authorized users.
Url:
DOI: 10.1186/s13046-019-1201-4
PubMed: 31138329
PubMed Central: 6540563
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Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Jiang, Xiuxing" sort="Jiang, Xiuxing" uniqKey="Jiang X" first="Xiuxing" last="Jiang">Xiuxing Jiang</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Hongwei" sort="Zhang, Hongwei" uniqKey="Zhang H" first="Hongwei" last="Zhang">Hongwei Zhang</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Gao, Ziyi" sort="Gao, Ziyi" uniqKey="Gao Z" first="Ziyi" last="Gao">Ziyi Gao</name><affiliation wicri:level="1"><nlm:aff id="Aff3">Greater Philadelphia Pharmacy, Philadelphia, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Greater Philadelphia Pharmacy, Philadelphia</wicri:regionArea></affiliation></author><author><name sortKey="Li, Yunong" sort="Li, Yunong" uniqKey="Li Y" first="Yunong" last="Li">Yunong Li</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Fu, Ruoqiu" sort="Fu, Ruoqiu" uniqKey="Fu R" first="Ruoqiu" last="Fu">Ruoqiu Fu</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Li, Lirong" sort="Li, Lirong" uniqKey="Li L" first="Lirong" last="Li">Lirong Li</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Li, Jie" sort="Li, Jie" uniqKey="Li J" first="Jie" last="Li">Jie Li</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Cui, Hongjuan" sort="Cui, Hongjuan" uniqKey="Cui H" first="Hongjuan" last="Cui">Hongjuan Cui</name><affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.263906.8</institution-id><institution>State Key Laboratory of Silkworm Genome 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Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0240 6969</institution-id><institution-id institution-id-type="GRID">grid.417409.f</institution-id><institution>Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education,</institution><institution>Zunyi Medical University,</institution></institution-wrap>Zunyi, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zunyi</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31138329</idno><idno type="pmc">6540563</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540563</idno><idno type="RBID">PMC:6540563</idno><idno type="doi">10.1186/s13046-019-1201-4</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000105</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000105</idno><idno type="wicri:Area/Pmc/Curation">000105</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000105</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">ROS-mediated activation and mitochondrial translocation of CaMKII contributes to Drp1-dependent mitochondrial fission and apoptosis in triple-negative breast cancer cells by isorhamnetin and chloroquine</title><author><name sortKey="Hu, Jinjiao" sort="Hu, Jinjiao" uniqKey="Hu J" first="Jinjiao" last="Hu">Jinjiao Hu</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Yanhao" sort="Zhang, Yanhao" uniqKey="Zhang Y" first="Yanhao" last="Zhang">Yanhao Zhang</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Jiang, Xiuxing" sort="Jiang, Xiuxing" uniqKey="Jiang X" first="Xiuxing" last="Jiang">Xiuxing Jiang</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Hongwei" sort="Zhang, Hongwei" uniqKey="Zhang H" first="Hongwei" last="Zhang">Hongwei Zhang</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Gao, Ziyi" sort="Gao, Ziyi" uniqKey="Gao Z" first="Ziyi" last="Gao">Ziyi Gao</name><affiliation wicri:level="1"><nlm:aff id="Aff3">Greater Philadelphia Pharmacy, Philadelphia, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Greater Philadelphia Pharmacy, Philadelphia</wicri:regionArea></affiliation></author><author><name sortKey="Li, Yunong" sort="Li, Yunong" uniqKey="Li Y" first="Yunong" last="Li">Yunong Li</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Fu, Ruoqiu" sort="Fu, Ruoqiu" uniqKey="Fu R" first="Ruoqiu" last="Fu">Ruoqiu Fu</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Li, Lirong" sort="Li, Lirong" uniqKey="Li L" first="Lirong" last="Li">Lirong Li</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Li, Jie" sort="Li, Jie" uniqKey="Li J" first="Jie" last="Li">Jie Li</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Cui, Hongjuan" sort="Cui, Hongjuan" uniqKey="Cui H" first="Hongjuan" last="Cui">Hongjuan Cui</name><affiliation wicri:level="1"><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="GRID">grid.263906.8</institution-id><institution>State Key Laboratory of Silkworm Genome Biology,</institution><institution>Southwest University,</institution></institution-wrap>2#Tiansheng Road, Beibei District, Chongqing, 400716 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>2#Tiansheng Road, Beibei District, Chongqing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="GRID">grid.263906.8</institution-id><institution>Medical Research Institute, Southwest University,</institution></institution-wrap>2#Tiansheng Road, Beibei District, Chongqing, 400716 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>2#Tiansheng Road, Beibei District, Chongqing</wicri:regionArea></affiliation></author><author><name sortKey="Gao, Ning" sort="Gao, Ning" uniqKey="Gao N" first="Ning" last="Gao">Ning Gao</name><affiliation wicri:level="1"><nlm:aff id="Aff1">College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0240 6969</institution-id><institution-id institution-id-type="GRID">grid.417409.f</institution-id><institution>Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education,</institution><institution>Zunyi Medical University,</institution></institution-wrap>Zunyi, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zunyi</wicri:regionArea></affiliation></author></analytic><series><title level="j">Journal of Experimental & Clinical Cancer Research : CR</title><idno type="ISSN">0392-9078</idno><idno type="eISSN">1756-9966</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><title>Background</title><p id="Par1">Triple-negative breast cancer (TNBC) is often aggressive and associated with a poor prognosis. Due to the lack of available targeted therapies and to problems of resistance with conventional chemotherapeutic agents, finding new treatments for TNBC remains a challenge and a better therapeutic strategy is urgently required.</p></sec><sec><title>Methods</title><p id="Par2">TNBC cells and xenograft mice were treated with a combination of chloroquine (CQ) and isorhamnetin (IH). Mitochondrial fission, apoptosis, and related signaling pathways were determined by flow cytometry, immunofluorescence, and related molecular biological techniques.</p></sec><sec><title>Results</title><p id="Par3">The inhibition of autophagy/mitophagy by CQ selectively enhances IH-induced mitochondrial fission and apoptosis in TNBC cells but not in estrogen-dependent breast cancer cells. These events were accompanied by mitochondrial translocation of Bax and the release of cytochrome c. Mechanistically, these effects were associated with oxidative stress-mediated phosphorylation of CaMKII (Thr286) and Drp1 (S616), and subsequent mitochondrial translocation of CaMKII and Drp1. The interruption of the CaMKII pathway by genetic approaches (e.g. CaMKII mutant or siRNA) attenuated combination-mediated mitochondrial fission and apoptosis. The combination of CQ/IH was a marked inhibitor tumor growth, inducing apoptosis in the TNBC xenograft mouse model in association with the activation of CaMKII and Drp1 (S616).</p></sec><sec><title>Conclusions</title><p id="Par4">Our study highlights the critical role of ROS-mediating CaMKII/Drp1 signaling in the regulation of mitochondrial fission and apoptosis induced by combination of CQ/IH. These findings also suggest that IH could potentially be further developed as a novel chemotherapeutic agent. Furthermore, a combination of IH with classic autophagy/mitophagy inhibitor could represent a novel therapeutic strategy for the treatment of TNBC.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (10.1186/s13046-019-1201-4) contains supplementary material, which is available to authorized users.</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Nagini, S" uniqKey="Nagini S">S Nagini</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dietze, Ec" uniqKey="Dietze E">EC Dietze</name></author><author><name sortKey="Sistrunk, C" uniqKey="Sistrunk C">C Sistrunk</name></author><author><name sortKey="Miranda Carboni, G" uniqKey="Miranda Carboni G">G Miranda-Carboni</name></author><author><name sortKey="O Regan, R" uniqKey="O Regan R">R O'Regan</name></author><author><name sortKey="Seewaldt, Vl" uniqKey="Seewaldt V">VL 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open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Exp Clin Cancer Res</journal-id><journal-id journal-id-type="iso-abbrev">J. Exp. Clin. Cancer Res</journal-id><journal-title-group><journal-title>Journal of Experimental & Clinical Cancer Research : CR</journal-title></journal-title-group><issn pub-type="ppub">0392-9078</issn><issn pub-type="epub">1756-9966</issn><publisher><publisher-name>BioMed Central</publisher-name><publisher-loc>London</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31138329</article-id><article-id pub-id-type="pmc">6540563</article-id><article-id pub-id-type="publisher-id">1201</article-id><article-id pub-id-type="doi">10.1186/s13046-019-1201-4</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research</subject></subj-group></article-categories><title-group><article-title>ROS-mediated activation and mitochondrial translocation of CaMKII contributes to Drp1-dependent mitochondrial fission and apoptosis in triple-negative breast cancer cells by isorhamnetin and chloroquine</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>Hu</surname><given-names>Jinjiao</given-names></name><address><email>13896194028@163.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Zhang</surname><given-names>Yanhao</given-names></name><address><email>406339261@qq.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Jiang</surname><given-names>Xiuxing</given-names></name><address><email>1119862476@qq.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Hongwei</given-names></name><address><email>zhwqz@hotmail.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Gao</surname><given-names>Ziyi</given-names></name><address><email>ziyi.gao13@gmail.com</email></address><xref ref-type="aff" rid="Aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Yunong</given-names></name><address><email>lyn90911@163.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Fu</surname><given-names>Ruoqiu</given-names></name><address><email>zxmfrq@163.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Lirong</given-names></name><address><email>598625482@qq.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Jie</given-names></name><address><email>550884945@qq.com</email></address><xref ref-type="aff" rid="Aff1">1</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Cui</surname><given-names>Hongjuan</given-names></name><address><email>hongjuan.cui@gmail.com</email></address><xref ref-type="aff" rid="Aff4">4</xref><xref ref-type="aff" rid="Aff5">5</xref></contrib><contrib contrib-type="author" corresp="yes"><name><surname>Gao</surname><given-names>Ning</given-names></name><address><email>gaoning59@163.com</email></address><xref ref-type="aff" rid="Aff1">1</xref><xref ref-type="aff" rid="Aff2">2</xref></contrib><aff id="Aff1"><label>1</label>College of Pharmacy, Army Medical University, 30 Gaotanyan Street, Shapingba District, Chongqing, 400038 China</aff><aff id="Aff2"><label>2</label><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0240 6969</institution-id><institution-id institution-id-type="GRID">grid.417409.f</institution-id><institution>Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education,</institution><institution>Zunyi Medical University,</institution></institution-wrap>Zunyi, China</aff><aff id="Aff3"><label>3</label>Greater Philadelphia Pharmacy, Philadelphia, USA</aff><aff id="Aff4"><label>4</label><institution-wrap><institution-id institution-id-type="GRID">grid.263906.8</institution-id><institution>State Key Laboratory of Silkworm Genome Biology,</institution><institution>Southwest University,</institution></institution-wrap>2#Tiansheng Road, Beibei District, Chongqing, 400716 China</aff><aff id="Aff5"><label>5</label><institution-wrap><institution-id institution-id-type="GRID">grid.263906.8</institution-id><institution>Medical Research Institute, Southwest University,</institution></institution-wrap>2#Tiansheng Road, Beibei District, Chongqing, 400716 China</aff></contrib-group><pub-date pub-type="epub"><day>28</day><month>5</month><year>2019</year></pub-date><pub-date pub-type="pmc-release"><day>28</day><month>5</month><year>2019</year></pub-date><pub-date pub-type="collection"><year>2019</year></pub-date><volume>38</volume><elocation-id>225</elocation-id><history><date date-type="received"><day>18</day><month>2</month><year>2019</year></date><date date-type="accepted"><day>30</day><month>4</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 distributed under the terms of the Creative Commons Attribution 4.0 International License (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/publicdomain/zero/1.0/">http://creativecommons.org/publicdomain/zero/1.0/</ext-link>) applies to the data made available in this article, unless otherwise stated.</license-p></license></permissions><abstract id="Abs1"><sec><title>Background</title><p id="Par1">Triple-negative breast cancer (TNBC) is often aggressive and associated with a poor prognosis. Due to the lack of available targeted therapies and to problems of resistance with conventional chemotherapeutic agents, finding new treatments for TNBC remains a challenge and a better therapeutic strategy is urgently required.</p></sec><sec><title>Methods</title><p id="Par2">TNBC cells and xenograft mice were treated with a combination of chloroquine (CQ) and isorhamnetin (IH). Mitochondrial fission, apoptosis, and related signaling pathways were determined by flow cytometry, immunofluorescence, and related molecular biological techniques.</p></sec><sec><title>Results</title><p id="Par3">The inhibition of autophagy/mitophagy by CQ selectively enhances IH-induced mitochondrial fission and apoptosis in TNBC cells but not in estrogen-dependent breast cancer cells. These events were accompanied by mitochondrial translocation of Bax and the release of cytochrome c. Mechanistically, these effects were associated with oxidative stress-mediated phosphorylation of CaMKII (Thr286) and Drp1 (S616), and subsequent mitochondrial translocation of CaMKII and Drp1. The interruption of the CaMKII pathway by genetic approaches (e.g. CaMKII mutant or siRNA) attenuated combination-mediated mitochondrial fission and apoptosis. The combination of CQ/IH was a marked inhibitor tumor growth, inducing apoptosis in the TNBC xenograft mouse model in association with the activation of CaMKII and Drp1 (S616).</p></sec><sec><title>Conclusions</title><p id="Par4">Our study highlights the critical role of ROS-mediating CaMKII/Drp1 signaling in the regulation of mitochondrial fission and apoptosis induced by combination of CQ/IH. These findings also suggest that IH could potentially be further developed as a novel chemotherapeutic agent. Furthermore, a combination of IH with classic autophagy/mitophagy inhibitor could represent a novel therapeutic strategy for the treatment of TNBC.</p></sec><sec><title>Electronic supplementary material</title><p>The online version of this article (10.1186/s13046-019-1201-4) contains supplementary material, which is available to authorized users.</p></sec></abstract><kwd-group xml:lang="en"><title>Keywords</title><kwd>Triple-negative breast cancer</kwd><kwd>Chloroquine</kwd><kwd>Isorhamnetin</kwd><kwd>Autophagy</kwd><kwd>Apoptosis</kwd><kwd>CaMKII</kwd><kwd>Drp1</kwd></kwd-group><funding-group><award-group><funding-source><institution>National Natural Science Foundation of China </institution></funding-source><award-id>31571425, 81402970; 81402013</award-id><principal-award-recipient><name><surname>Gao</surname><given-names>Ning</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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