Natural Naphthohydroquinone Dimer Rubioncolin C Exerts Anti-Tumor Activity by Inducing Apoptotic and Autophagic Cell Death and Inhibiting the NF-κB and Akt/mTOR/P70S6K Pathway in Human Cancer Cells
Identifieur interne : 000478 ( Pmc/Curation ); précédent : 000477; suivant : 000479Natural Naphthohydroquinone Dimer Rubioncolin C Exerts Anti-Tumor Activity by Inducing Apoptotic and Autophagic Cell Death and Inhibiting the NF-κB and Akt/mTOR/P70S6K Pathway in Human Cancer Cells
Auteurs : Jia Wang ; Ling Li ; Jing Wang ; Lihua Song ; Ninghua Tan ; Zhe WangSource :
- Cells [ 2073-4409 ] ; 2019.
Abstract
Naphthohydroquinone dimers isolated from
Url:
DOI: 10.3390/cells8121593
PubMed: 31817918
PubMed Central: 6953124
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Natural Naphthohydroquinone Dimer Rubioncolin C Exerts Anti-Tumor Activity by Inducing Apoptotic and Autophagic Cell Death and Inhibiting the NF-κB and Akt/mTOR/P70S6K Pathway in Human Cancer Cells</title><author><name sortKey="Wang, Jia" sort="Wang, Jia" uniqKey="Wang J" first="Jia" last="Wang">Jia Wang</name></author><author><name sortKey="Li, Ling" sort="Li, Ling" uniqKey="Li L" first="Ling" last="Li">Ling Li</name></author><author><name sortKey="Wang, Jing" sort="Wang, Jing" uniqKey="Wang J" first="Jing" last="Wang">Jing Wang</name></author><author><name sortKey="Song, Lihua" sort="Song, Lihua" uniqKey="Song L" first="Lihua" last="Song">Lihua Song</name></author><author><name sortKey="Tan, Ninghua" sort="Tan, Ninghua" uniqKey="Tan N" first="Ninghua" last="Tan">Ninghua Tan</name></author><author><name sortKey="Wang, Zhe" sort="Wang, Zhe" uniqKey="Wang Z" first="Zhe" last="Wang">Zhe Wang</name></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31817918</idno><idno type="pmc">6953124</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953124</idno><idno type="RBID">PMC:6953124</idno><idno type="doi">10.3390/cells8121593</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000478</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000478</idno><idno type="wicri:Area/Pmc/Curation">000478</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000478</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Natural Naphthohydroquinone Dimer Rubioncolin C Exerts Anti-Tumor Activity by Inducing Apoptotic and Autophagic Cell Death and Inhibiting the NF-κB and Akt/mTOR/P70S6K Pathway in Human Cancer Cells</title><author><name sortKey="Wang, Jia" sort="Wang, Jia" uniqKey="Wang J" first="Jia" last="Wang">Jia Wang</name></author><author><name sortKey="Li, Ling" sort="Li, Ling" uniqKey="Li L" first="Ling" last="Li">Ling Li</name></author><author><name sortKey="Wang, Jing" sort="Wang, Jing" uniqKey="Wang J" first="Jing" last="Wang">Jing Wang</name></author><author><name sortKey="Song, Lihua" sort="Song, Lihua" uniqKey="Song L" first="Lihua" last="Song">Lihua Song</name></author><author><name sortKey="Tan, Ninghua" sort="Tan, Ninghua" uniqKey="Tan N" first="Ninghua" last="Tan">Ninghua Tan</name></author><author><name sortKey="Wang, Zhe" sort="Wang, Zhe" uniqKey="Wang Z" first="Zhe" last="Wang">Zhe Wang</name></author></analytic><series><title level="j">Cells</title><idno type="eISSN">2073-4409</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>Naphthohydroquinone dimers isolated from <italic>Rubia</italic> plants have garnered more attention due to their distinctive chemical structures and intriguing bioactivities. In our previous studies, we obtained ten naphthohydroquinone dimers containing seven novel ones and found that most of them possessed anti-tumor activities, especially rubioncolin C. However, the underlying mechanism remains unknown. In this study, we focused on rubioncolin C and found that it could inhibit the growth of cancer cell lines with IC<sub>50</sub> values between 1.14 and 9.93 μM. Further experiments demonstrated that rubioncolin C induced apoptotic and autophagic cell death and inhibited the Akt/mTOR/P70S6K signaling pathway in HCT116 and HepG2 cells. Moreover, we observed that rubioncolin C inhibited the TNF-α- and LPS-induced NF-κB activation upstream of the p65 protein, which contributed to rubioncolin C-induced cell death. Rubioncolin C could also prevent LPS-induced endotoxin shock in vivo. Moreover, rubioncolin C suppressed tumor growth through inducing apoptosis and autophagy and inactivating NF-κB in vivo. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cells</journal-id><journal-id journal-id-type="iso-abbrev">Cells</journal-id><journal-id journal-id-type="publisher-id">cells</journal-id><journal-title-group><journal-title>Cells</journal-title></journal-title-group><issn pub-type="epub">2073-4409</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31817918</article-id><article-id pub-id-type="pmc">6953124</article-id><article-id pub-id-type="doi">10.3390/cells8121593</article-id><article-id pub-id-type="publisher-id">cells-08-01593</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Natural Naphthohydroquinone Dimer Rubioncolin C Exerts Anti-Tumor Activity by Inducing Apoptotic and Autophagic Cell Death and Inhibiting the NF-κB and Akt/mTOR/P70S6K Pathway in Human Cancer Cells</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Jia</given-names></name><xref ref-type="author-notes" rid="fn1-cells-08-01593">†</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Ling</given-names></name><xref ref-type="author-notes" rid="fn1-cells-08-01593">†</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Jing</given-names></name></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-9005-2231</contrib-id><name><surname>Song</surname><given-names>Lihua</given-names></name></contrib><contrib contrib-type="author"><name><surname>Tan</surname><given-names>Ninghua</given-names></name><xref rid="c1-cells-08-01593" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-7854-8207</contrib-id><name><surname>Wang</surname><given-names>Zhe</given-names></name><xref rid="c1-cells-08-01593" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-cells-08-01593">Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China;<email>1731020094@stu.cpu.edu.cn</email> (J.W.);<email>1821020435@stu.cpu.edu.cn</email> (L.L.);<email>18851107621@163.com</email> (J.W.);<email>songlihua4835@163.com</email> (L.S.)</aff><author-notes><corresp id="c1-cells-08-01593"><label>*</label>Correspondence: <email>nhtan@cpu.edu.cn</email> (N.T.); <email>wangzhe@cpu.edu.cn</email> (Z.W.); Tel.: +86-25-86185772 (N.T. & Z.W.)</corresp><fn id="fn1-cells-08-01593"><label>†</label><p>These authors contributed equally to this work.</p></fn></author-notes><pub-date pub-type="epub"><day>07</day><month>12</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>12</month><year>2019</year></pub-date><volume>8</volume><issue>12</issue><elocation-id>1593</elocation-id><history><date date-type="received"><day>29</day><month>10</month><year>2019</year></date><date date-type="accepted"><day>04</day><month>12</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) 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>).</license-p></license></permissions><abstract><p>Naphthohydroquinone dimers isolated from <italic>Rubia</italic> plants have garnered more attention due to their distinctive chemical structures and intriguing bioactivities. In our previous studies, we obtained ten naphthohydroquinone dimers containing seven novel ones and found that most of them possessed anti-tumor activities, especially rubioncolin C. However, the underlying mechanism remains unknown. In this study, we focused on rubioncolin C and found that it could inhibit the growth of cancer cell lines with IC<sub>50</sub> values between 1.14 and 9.93 μM. Further experiments demonstrated that rubioncolin C induced apoptotic and autophagic cell death and inhibited the Akt/mTOR/P70S6K signaling pathway in HCT116 and HepG2 cells. Moreover, we observed that rubioncolin C inhibited the TNF-α- and LPS-induced NF-κB activation upstream of the p65 protein, which contributed to rubioncolin C-induced cell death. Rubioncolin C could also prevent LPS-induced endotoxin shock in vivo. Moreover, rubioncolin C suppressed tumor growth through inducing apoptosis and autophagy and inactivating NF-κB in vivo. These findings clarify the anti-tumor mechanism of rubioncolin C using biochemical techniques and pharmacological models and might contribute to the future development of rubioncolin C as a new therapeutic agent for treating cancer.</p></abstract><kwd-group><kwd>naphthohydroquinone dimer</kwd><kwd>rubioncolin C</kwd><kwd>anti-tumor activity</kwd><kwd>apoptosis</kwd><kwd>autophagy</kwd><kwd>NF-κB pathway</kwd><kwd>Akt/mTOR/P70S6K pathway</kwd></kwd-group></article-meta></front><floats-group><fig id="cells-08-01593-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>RC inhibits the growth of cancer cell lines. (<bold>A</bold>) The chemical structure and HPLC analysis of RC. (<bold>B</bold>,<bold>C</bold>) RC inhibited the growth of cancer cell lines and their IC<sub>50</sub> values. HCT116, SW620, HT29, SW480, HCT15, T84, RKO, SMMC-7721, HepG2, or Bel-7402 cells were seeded in 96-well plates. After 24 h, the cells were incubated with various concentrations of RC for 48 h. The cell viability was determined by MTS assay. The data are presented as the means ± S.D. from three independent experiments. (<bold>D</bold>) RC influenced the expression of cell cycle regulating proteins. HepG2 cells were incubated with various concentrations of RC for 24 h. The cell lysates were prepared and subjected to a Western blot analysis with the indicated antibodies.</p></caption><graphic xlink:href="cells-08-01593-g001"></graphic></fig><fig id="cells-08-01593-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>RC induces apoptosis in HCT116 and HepG2 cells. (<bold>A</bold>,<bold>B</bold>) RC influenced the expression of apoptosis-related proteins. HCT116 or HepG2 cells were incubated with various concentrations of RC for 24, 12, or 6 h and the expression of apoptosis-related proteins was measured by Western blotting. (<bold>C</bold>,<bold>D</bold>) HepG2 cells were incubated with various concentrations of RC for 24 h and the cells were co-stained with Annexin V/PI to determine apoptosis by flow cytometry (<bold>C</bold>), or stained with JC-1 and photographed by fluorescence (<bold>D</bold>). (<bold>E</bold>) HepG2 cells were incubated with or without Z-VAD-FMK (25 μM) for 1 h, and then treated with various concentrations of RC for 24 h. Cell viability was determined by MTS assay. The data are presented as the means ± S.D. from three independent experiments. *, <italic>p</italic> < 0.05; **, <italic>p</italic> < 0.01.</p></caption><graphic xlink:href="cells-08-01593-g002"></graphic></fig><fig id="cells-08-01593-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>RC induces autophagic cell death by inhibiting the Akt/mTOR/P70S6K signaling pathway in HCT116 and HepG2 cells. (<bold>A</bold>,<bold>B</bold>) RC influenced the expression of autophagy-related proteins. HCT116 or HepG2 cells were treated with various concentrations of RC for 24, 12, or 6 h, and the expression of autophagy-related proteins was determined by Western blotting. (<bold>C</bold>) RC increased the aggregation of GFP-LC3 dots. HepG2 cells were transfected with GFP-LC3 plasmid. Twenty-four hours after transfection, the cells were incubated with 10 μM RC for 12 h, and the GFP-LC3B distribution was analyzed and quantified with a fluorescence microscope. Only cells with more than five puncta were counted. (<bold>D</bold>) RC increased the amounts of autophagic vesicles. HepG2 cells were incubated with or without 3-MA (3 mM) or CQ (25 μM) for 1 h, and then treated with various concentrations of RC for 12 h. After being stained with MDC for 30 min at 37 <sup>o</sup>C, cells were imaged with a florescence microscope. (<bold>E</bold>) RC increased the amounts of lysosome or induced lysosome aggregation. Similarly to (<bold>D</bold>), cells were stained with Lysotracker red for 30 min at 37 <sup>o</sup>C and captured by florescence microscope. (<bold>F</bold>–<bold>G</bold>) RC induced autophagic cell death. HCT116 were incubated with or without 3-MA (3 mM) or CQ (25 μM) for 1 h, and then treated with various concentrations of RC for 24 h. The cell viability was evaluated by MTS assay (<bold>F</bold>), or the expression of related proteins was determined by Western blotting (<bold>G</bold>). (<bold>H</bold>) RC decreased the expression of mTOR, phospho-mTOR, Akt, phospho-Akt, and phospho-P70S6K. HCT116 or HepG2 cells were treated with various concentrations of RC for 24 h; the cell lysates were prepared and Western blotting with the indicated antibodies. The data in (<bold>C</bold>) and (<bold>F</bold>) are presented as the means ± S.D. from three independent experiments. *, <italic>p</italic> < 0.05; **, <italic>p</italic> < 0.01, ***, <italic>p</italic> < 0.001.</p></caption><graphic xlink:href="cells-08-01593-g003"></graphic></fig><fig id="cells-08-01593-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>RC inhibits the activation of NF-κB signaling pathway. (<bold>A</bold>) RC inhibited the NF-κB signaling pathway. HEK293T cells were transfected with the 5× κB-luciferase and pTK-Renilla reporters. Twenty-four hours after transfection, the cells were treated with various concentrations of RC for 6 h, and then incubated with 10 ng/mL TNF-α for 4 h before the luciferase activity assay and MTS assay. (<bold>B</bold>,<bold>C</bold>) RC reduced TNF-α-induced IκBα phosphorylation, IκBα degradation and p65 phosphorylation. HCT116 or HepG2 cells were incubated with various concentrations of RC for 24 h and treated with 10 ng/mL TNF-α for 10 min. The cell lysates were prepared and subjected to a Western blotting analysis with the indicated antibodies. (<bold>D</bold>) RC inhibited TNF-α-induced expression of NF-κB target genes. HCT116 or HepG2 cells were treated with various concentrations of RC for 24 h and stimulated with 10 ng/mL TNF-α for 2 h. The expression of the NF-κB target genes, <italic>IL-8</italic> and <italic>A20</italic> were measured by quantitative RT-PCR and normalized to GADPH expression. (<bold>E</bold>) RC inhibited TNF-α-induced IL-8 production. HepG2 cells were treated with RC for 24 h before treatment with 10 ng/mL TNF-α for 4 h. The culture supernatant was collected and subjected to ELISA analysis. (<bold>F</bold>,<bold>G</bold>) RC inhibited the TNF-α-induced nuclear translocation of p65. HCT116 or HepG2 cells were incubated with 10 μM RC for 6 h and treated with 10 ng/mL TNF-α for 15 min, and then subjected to an immunocytochemical analysis or a nuclear and cytoplasmic protein extraction analysis. (<bold>H</bold>,<bold>I</bold>) RC inhibited LPS-induced IκBα phosphorylation, IκBα degradation, p65 phosphorylation, and <italic>IL-6</italic> mRNA expression. RAW264.7 cells were treated with various concentrations of RC for 24 h and treated with 1 μg/mL LPS for 3 h. The proteins and <italic>IL-6</italic> mRNA expression were determined. (<bold>J</bold>,<bold>K</bold>) RC inhibited LPS-induced IL-6 and NO production. RAW264.7 cells were treated with various concentrations of RC for 24 h and treated with 1 μg/mL LPS for 24 h. The production of IL-6 and NO was measured. The data in (<bold>D</bold>), (<bold>E</bold>), and (<bold>I</bold>–<bold>K</bold>) are presented as the means ± S.D. from three independent experiments. *, <italic>p</italic> < 0.05; **, <italic>p</italic> < 0.01; ***, <italic>p</italic> < 0.001.</p></caption><graphic xlink:href="cells-08-01593-g004"></graphic></fig><fig id="cells-08-01593-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>RC prevents endotoxic shock in BALB/c mice. (<bold>A</bold>–<bold>D</bold>) RC prevents endotoxic shock in vivo. Mice (<italic>n</italic> = 6 per group) were intraperitoneally injected with control microemulsion or RC microemulsion for 4 h before intraperitoneal injection of LPS (10 mg/kg). One hour later, the relative levels of <italic>TNF-α</italic> and <italic>IL-6</italic> mRNAs in the liver were evaluated by quantitative RT-PCR (<bold>A</bold>,<bold>B</bold>), the serum TNF-α and IL-6 levels were determined by ELISA (<bold>C</bold>,<bold>D</bold>). (<bold>E</bold>) RC improved animal survival. Mice (<italic>n</italic> = 15 per group) were intravenously injected with control microemulsion or RC microemulsion (20 mg/kg) for 4 h before intraperitoneal injection of LPS (20 mg/kg). Animal survival was recorded in two or four h intervals (<italic>p</italic> = 0.0155, Mantel-Cox test). The data are presented as the means ± S.D. *, <italic>p</italic> < 0.05; **, <italic>p</italic> < 0.01.</p></caption><graphic xlink:href="cells-08-01593-g005"></graphic></fig><fig id="cells-08-01593-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>RC represses NF-κB activation upstream of the p65 protein and contributes to cell death. (<bold>A</bold>) RC inhibits NF-κB activation caused by overexpressing NF-κB-associated key proteins. The indicated plasmids were transfected into HEK293T cells together with the 5× κB-luciferase and pTK-Renilla reporters. Twenty-four hours after transfection, the cells were incubated with 10 μM RC for 6 h before luciferase assays were performed. (<bold>B</bold>–<bold>D</bold>) RC induced cell death involving in NF-κB pathway. HepG2 cells were incubated in the presence or absence of TNF-α (20 ng/mL, 30 min) prior to treatment with 5 μM RC for 24 h. The cell viability was evaluated by MTS assay (<bold>B</bold>). Similarly to (<bold>B</bold>), cells were transfected with HA-p65 plasmid for 24 h, then incubated with 5 μM RC for 24 h. The cell viability was also evaluated by MTS assay (<bold>C</bold>,<bold>D</bold>). *, <italic>p</italic> < 0.05; **, <italic>p</italic> < 0.01; ***, <italic>p</italic> < 0.001.</p></caption><graphic xlink:href="cells-08-01593-g006"></graphic></fig><fig id="cells-08-01593-f007" orientation="portrait" position="float"><label>Figure 7</label><caption><p>RC inhibits tumor growth and induces apoptosis and autophagy with the inhibition of NF-κB in vivo. (<bold>A</bold>–<bold>C</bold>) RC inhibited the growth of HCT116 and HepG2 xenograft tumors. Female athymic nude BALB/c mice bearing HCT116 (<italic>n</italic> = 5) or HepG2 (<italic>n</italic> = 5) xenograft tumors were intraperitoneally injected with control microemulsion or RC microemulsion every other day. 5-FU (10 mg/kg) group as positive control. Effects of RC on the growth curves of subcutaneous xenografts (<bold>A</bold>,<bold>B</bold>) and on the tumor weight (<bold>C</bold>) in the HCT116 and HepG2 models. (<bold>D</bold>) The expression of the apoptosis and autophagy related proteins in HepG2 tumor tissues was evaluated by an immunohistochemistry analysis. (<bold>E</bold>) The expression of the NF-κB target genes, <italic>IL-8</italic>, <italic>CXCL-1</italic>, <italic>A20</italic> and <italic>MCP-1</italic> in HepG2 tumor tissues was determined by quantitative RT-PCR and normalized to <italic>GADPH</italic> expression. *, <italic>p</italic> < 0.05; **, <italic>p</italic> < 0.01; ***, <italic>p</italic> < 0.001.</p></caption><graphic xlink:href="cells-08-01593-g007"></graphic></fig><fig id="cells-08-01593-f008" orientation="portrait" position="float"><label>Figure 8</label><caption><p>Analysis of potential side effects for treated with RC. (<bold>A</bold>,<bold>B</bold>) The change curves of body weights of BALB/c bearing HCT116 (<italic>n</italic> = 5) (<bold>A</bold>) or HepG2 (<italic>n</italic> = 5) (<bold>B</bold>) xenograft tumors. (<bold>C</bold>) Representative hematoxylin-eosin staining of heart, kidney, spleen, lung and liver from vehicle- and RC-treated groups. (<bold>D</bold>) The evaluation of serum ALT, AST and creatine kinase for vehicle- and RC-treated groups.</p></caption><graphic xlink:href="cells-08-01593-g008"></graphic></fig><fig id="cells-08-01593-f009" orientation="portrait" position="float"><label>Figure 9</label><caption><p>Proposed anti-tumor mechanism of rubioncolin C.</p></caption><graphic xlink:href="cells-08-01593-g009"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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