A Derivate of Benzimidazole-Isoquinolinone Induces SKP2 Transcriptional Inhibition to Exert Anti-Tumor Activity in Glioblastoma Cells
Identifieur interne : 000719 ( Pmc/Curation ); précédent : 000718; suivant : 000720A Derivate of Benzimidazole-Isoquinolinone Induces SKP2 Transcriptional Inhibition to Exert Anti-Tumor Activity in Glioblastoma Cells
Auteurs : He-Ying Chen [République populaire de Chine] ; Liu-Jun He [République populaire de Chine] ; Shi-Qiang Li [République populaire de Chine] ; Ya-Jun Zhang [République populaire de Chine] ; Jiu-Hong Huang [République populaire de Chine] ; Hong-Xia Qin [République populaire de Chine] ; Juan-Li Wang [République populaire de Chine] ; Qian-Yin Li [République populaire de Chine] ; Dong-Lin Yang [République populaire de Chine]Source :
- Molecules [ 1420-3049 ] ; 2019.
Abstract
We have previously shown that compound-7g inhibits colorectal cancer cell proliferation and survival by inducing cell cycle arrest and PI3K/AKT/mTOR pathway blockage. However, whether it has the ability to exert antitumor activity in other cancer cells and what is the exact molecular mechanism for its antiproliferation effect remained to be determined. In the present study, compound-7g exhibited strong activity in suppressing proliferation and growth of glioblastoma cells. The inhibitor selectively downregulated F-box protein SKP2 expression and upregulated cell cycle inhibitor p27, and then resulted in G1 cell cycle arrest. Mechanism analysis revealed that compound-7g also provokes the down-regulation of E2F-1, which acts as a transcriptional factor of SKP2. Further results indicated that compound-7g induced an increase of LC3B-II and p62, which causes a suppression of fusion between autophagosome and lysosome. Moreover, compound-7g mediated autophagic flux blockage promoted accumulation of ubiquitinated proteins and then led to endoplasmic reticulum stress. Our study thus demonstrated that pharmacological inactivation of E2F-1-SKP2-p27 axis is a promising target for restricting cancer progression.
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DOI: 10.3390/molecules24152722
PubMed: 31357480
PubMed Central: 6695871
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Shi Qiang" uniqKey="Li S" first="Shi-Qiang" last="Li">Shi-Qiang Li</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Ya Jun" sort="Zhang, Ya Jun" uniqKey="Zhang Y" first="Ya-Jun" last="Zhang">Ya-Jun Zhang</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation></author><author><name sortKey="Huang, Jiu Hong" sort="Huang, Jiu Hong" uniqKey="Huang J" first="Jiu-Hong" last="Huang">Jiu-Hong Huang</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation></author><author><name sortKey="Qin, Hong Xia" sort="Qin, Hong Xia" uniqKey="Qin H" first="Hong-Xia" last="Qin">Hong-Xia Qin</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Juan Li" sort="Wang, Juan Li" uniqKey="Wang J" first="Juan-Li" last="Wang">Juan-Li Wang</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation></author><author><name sortKey="Li, Qian Yin" sort="Li, Qian Yin" uniqKey="Li Q" first="Qian-Yin" last="Li">Qian-Yin Li</name><affiliation wicri:level="1"><nlm:aff id="af1-molecules-24-02722">Division of Molecular Nephrology and the Creative Training Center for Undergraduates, the Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Division of Molecular Nephrology and the Creative Training Center for Undergraduates, the Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016</wicri:regionArea></affiliation></author><author><name sortKey="Yang, Dong Lin" sort="Yang, Dong Lin" uniqKey="Yang D" first="Dong-Lin" last="Yang">Dong-Lin Yang</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31357480</idno><idno type="pmc">6695871</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695871</idno><idno type="RBID">PMC:6695871</idno><idno type="doi">10.3390/molecules24152722</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000719</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000719</idno><idno type="wicri:Area/Pmc/Curation">000719</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000719</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A Derivate of Benzimidazole-Isoquinolinone Induces SKP2 Transcriptional Inhibition to Exert Anti-Tumor Activity in Glioblastoma Cells</title><author><name sortKey="Chen, He Ying" sort="Chen, He Ying" uniqKey="Chen H" first="He-Ying" last="Chen">He-Ying Chen</name><affiliation wicri:level="1"><nlm:aff id="af1-molecules-24-02722">Division of Molecular Nephrology and the Creative Training Center for Undergraduates, the Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Division of Molecular Nephrology and the Creative Training Center for Undergraduates, the Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-molecules-24-02722">The Undergraduates Class of 2016 entry the College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>The Undergraduates Class of 2016 entry the College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016</wicri:regionArea></affiliation></author><author><name sortKey="He, Liu Jun" sort="He, Liu Jun" uniqKey="He L" first="Liu-Jun" last="He">Liu-Jun He</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation></author><author><name sortKey="Li, Shi Qiang" sort="Li, Shi Qiang" uniqKey="Li S" first="Shi-Qiang" last="Li">Shi-Qiang Li</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation></author><author><name sortKey="Zhang, Ya Jun" sort="Zhang, Ya Jun" uniqKey="Zhang Y" first="Ya-Jun" last="Zhang">Ya-Jun Zhang</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation></author><author><name sortKey="Huang, Jiu Hong" sort="Huang, Jiu Hong" uniqKey="Huang J" first="Jiu-Hong" last="Huang">Jiu-Hong Huang</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation></author><author><name sortKey="Qin, Hong Xia" sort="Qin, Hong Xia" uniqKey="Qin H" first="Hong-Xia" last="Qin">Hong-Xia Qin</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation></author><author><name sortKey="Wang, Juan Li" sort="Wang, Juan Li" uniqKey="Wang J" first="Juan-Li" last="Wang">Juan-Li Wang</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation></author><author><name sortKey="Li, Qian Yin" sort="Li, Qian Yin" uniqKey="Li Q" first="Qian-Yin" last="Li">Qian-Yin Li</name><affiliation wicri:level="1"><nlm:aff id="af1-molecules-24-02722">Division of Molecular Nephrology and the Creative Training Center for Undergraduates, the Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Division of Molecular Nephrology and the Creative Training Center for Undergraduates, the Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016</wicri:regionArea></affiliation></author><author><name sortKey="Yang, Dong Lin" sort="Yang, Dong Lin" uniqKey="Yang D" first="Dong-Lin" last="Yang">Dong-Lin Yang</name><affiliation wicri:level="1"><nlm:aff id="af2-molecules-24-02722">Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160</wicri:regionArea></affiliation></author></analytic><series><title level="j">Molecules</title><idno type="eISSN">1420-3049</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 shown that compound-7g inhibits colorectal cancer cell proliferation and survival by inducing cell cycle arrest and PI3K/AKT/mTOR pathway blockage. However, whether it has the ability to exert antitumor activity in other cancer cells and what is the exact molecular mechanism for its antiproliferation effect remained to be determined. In the present study, compound-7g exhibited strong activity in suppressing proliferation and growth of glioblastoma cells. The inhibitor selectively downregulated F-box protein SKP2 expression and upregulated cell cycle inhibitor p27, and then resulted in G1 cell cycle arrest. Mechanism analysis revealed that compound-7g also provokes the down-regulation of E2F-1, which acts as a transcriptional factor of SKP2. Further results indicated that compound-7g induced an increase of LC3B-II and p62, which causes a suppression of fusion between autophagosome and lysosome. Moreover, compound-7g mediated autophagic flux blockage promoted accumulation of ubiquitinated proteins and then led to endoplasmic reticulum stress. Our study thus demonstrated that pharmacological inactivation of E2F-1-SKP2-p27 axis is a promising target for restricting cancer progression.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Stupp, R" uniqKey="Stupp R">R. Stupp</name></author><author><name sortKey="Mason, W P" uniqKey="Mason W">W.P. Mason</name></author><author><name sortKey="Van Den Bent, M J" uniqKey="Van Den Bent M">M.J. Van Den Bent</name></author><author><name sortKey="Weller, M" uniqKey="Weller M">M. Weller</name></author><author><name sortKey="Fisher, B" uniqKey="Fisher B">B. Fisher</name></author><author><name sortKey="Taphoorn, M J" uniqKey="Taphoorn M">M.J. Taphoorn</name></author><author><name sortKey="Belanger, K" uniqKey="Belanger K">K. Belanger</name></author><author><name sortKey="Brandes, A A" uniqKey="Brandes A">A.A. Brandes</name></author><author><name sortKey="Marosi, C" uniqKey="Marosi C">C. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Molecules</journal-id><journal-id journal-id-type="iso-abbrev">Molecules</journal-id><journal-id journal-id-type="publisher-id">molecules</journal-id><journal-title-group><journal-title>Molecules</journal-title></journal-title-group><issn pub-type="epub">1420-3049</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31357480</article-id><article-id pub-id-type="pmc">6695871</article-id><article-id pub-id-type="doi">10.3390/molecules24152722</article-id><article-id pub-id-type="publisher-id">molecules-24-02722</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>A Derivate of Benzimidazole-Isoquinolinone Induces SKP2 Transcriptional Inhibition to Exert Anti-Tumor Activity in Glioblastoma Cells</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Chen</surname><given-names>He-ying</given-names></name><xref ref-type="aff" rid="af1-molecules-24-02722">1</xref><xref ref-type="aff" rid="af2-molecules-24-02722">2</xref><xref ref-type="aff" rid="af3-molecules-24-02722">3</xref><xref ref-type="author-notes" rid="fn1-molecules-24-02722">†</xref></contrib><contrib contrib-type="author"><name><surname>He</surname><given-names>Liu-jun</given-names></name><xref ref-type="aff" rid="af2-molecules-24-02722">2</xref><xref ref-type="author-notes" rid="fn1-molecules-24-02722">†</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Shi-qiang</given-names></name><xref ref-type="aff" rid="af2-molecules-24-02722">2</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Ya-jun</given-names></name><xref ref-type="aff" rid="af2-molecules-24-02722">2</xref></contrib><contrib contrib-type="author"><name><surname>Huang</surname><given-names>Jiu-hong</given-names></name><xref ref-type="aff" rid="af2-molecules-24-02722">2</xref></contrib><contrib contrib-type="author"><name><surname>Qin</surname><given-names>Hong-xia</given-names></name><xref ref-type="aff" rid="af2-molecules-24-02722">2</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Juan-li</given-names></name><xref ref-type="aff" rid="af2-molecules-24-02722">2</xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Qian-yin</given-names></name><xref ref-type="aff" rid="af1-molecules-24-02722">1</xref><xref rid="c1-molecules-24-02722" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Dong-lin</given-names></name><xref ref-type="aff" rid="af2-molecules-24-02722">2</xref><xref rid="c1-molecules-24-02722" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-molecules-24-02722"><label>1</label>Division of Molecular Nephrology and the Creative Training Center for Undergraduates, the Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China</aff><aff id="af2-molecules-24-02722"><label>2</label>Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing 402160, China</aff><aff id="af3-molecules-24-02722"><label>3</label>The Undergraduates Class of 2016 entry the College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China</aff><author-notes><corresp id="c1-molecules-24-02722"><label>*</label>Correspondence: <email>liqianyin@cqmu.edu.cn</email> (Q.-y.L.); <email>dlyang09@126.com</email> (D.-l.Y.)</corresp><fn id="fn1-molecules-24-02722"><label>†</label><p>Both authors contributed equally.</p></fn></author-notes><pub-date pub-type="epub"><day>26</day><month>7</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>8</month><year>2019</year></pub-date><volume>24</volume><issue>15</issue><elocation-id>2722</elocation-id><history><date date-type="received"><day>12</day><month>7</month><year>2019</year></date><date date-type="accepted"><day>26</day><month>7</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>We have previously shown that compound-7g inhibits colorectal cancer cell proliferation and survival by inducing cell cycle arrest and PI3K/AKT/mTOR pathway blockage. However, whether it has the ability to exert antitumor activity in other cancer cells and what is the exact molecular mechanism for its antiproliferation effect remained to be determined. In the present study, compound-7g exhibited strong activity in suppressing proliferation and growth of glioblastoma cells. The inhibitor selectively downregulated F-box protein SKP2 expression and upregulated cell cycle inhibitor p27, and then resulted in G1 cell cycle arrest. Mechanism analysis revealed that compound-7g also provokes the down-regulation of E2F-1, which acts as a transcriptional factor of SKP2. Further results indicated that compound-7g induced an increase of LC3B-II and p62, which causes a suppression of fusion between autophagosome and lysosome. Moreover, compound-7g mediated autophagic flux blockage promoted accumulation of ubiquitinated proteins and then led to endoplasmic reticulum stress. Our study thus demonstrated that pharmacological inactivation of E2F-1-SKP2-p27 axis is a promising target for restricting cancer progression.</p></abstract><kwd-group><kwd>compound-7g</kwd><kwd>glioblastoma</kwd><kwd>SKP2</kwd><kwd>E2F-1</kwd><kwd>cell cycle</kwd><kwd>autophagic flux</kwd></kwd-group></article-meta></front><floats-group><fig id="molecules-24-02722-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Compound-7g suppresses glioblastoma cells proliferation and viability. (<bold>A</bold>) The chemical structure of compound-7g. (<bold>B</bold>) Digital phase contrast images of LN229 and U87 cells after treatment with compound-7g. Images were captured in high content analysis system-operetta CLSTM. Scale bar, 10 μm. (<bold>C</bold>) Cell growth curve was performed following indicated concentrations of compound-7g treatment. The cell number was analyzed with high content analysis system-operetta CLSTM at an interval of 6h. (<bold>D</bold>) Colony formation assay was performed to evaluate cell growth in vitro after treatment with the indicated concentrations of compound-10# for 14 days. All data were demonstrated as the mean ± SD of three independent experiments.</p></caption><graphic xlink:href="molecules-24-02722-g001"></graphic></fig><fig id="molecules-24-02722-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Compound-7g induces transcriptional repression of <italic>skp2</italic> by promoting E2F-1 degradation. (<bold>A</bold>) Immunoblotting was explored to evaluate the expression of SKP2, p27 and E2F-1 after treatment with compound-7g in LN229 and U87 cells. (<bold>B</bold>) Immunoblotting was performed to detect the effect of combination between compound-7g and MG132 on SKP2 expression. (<bold>C</bold>) The mRNA expression level of <italic>skp2</italic> was analyzed by real-time PCR. Actin was used as an internal control in the mRNA analysis experiments. (<bold>D</bold>) Immunofluorescence was performed to further detect the E2F-1 expression as well as localization change. The images were captured by high content analysis system-operetta CLS™. Scale bar: 10 μm. (<bold>E</bold>) Histograms represent the percentages of nuclear E2F-1 positive cells in (<bold>D</bold>). The data are shown as the means ± SD (n = 3). * <italic>P</italic> < 0.05; ** <italic>P</italic> < 0.01; *** <italic>P</italic> < 0.001 compared with the control group.</p></caption><graphic xlink:href="molecules-24-02722-g002"></graphic></fig><fig id="molecules-24-02722-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Compound-7g results in the G1 cell cycle arrest in glioblastoma cells. (<bold>A</bold>,<bold>B</bold>) The cell cycle of LN229 and U87 cells was measured by flow cytometry in the presence of compound-7g and the percentages of cell population in different periods were quantitated with three independent experiments. (<bold>C</bold>) Impact of compound-7g on the expression levels of G1 phase related proteins in LN229 and U87cells was determined by immunoblotting assay. Tubulin was used as a loading control.</p></caption><graphic xlink:href="molecules-24-02722-g003"></graphic></fig><fig id="molecules-24-02722-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Compound-7g inhibits the autophagic flux in both LN229 and U87 cells. (<bold>A</bold>) LC3B-II and p62 were detected using immunoblotting to evaluate the effect of compound-7g on autophagy. (<bold>B</bold>) Immunofluorescence was performed to analyze LC3B after exposing to the indicated concentrations of compound-7g. Scale bar: 10 μm. (<bold>C</bold>) Both LN229 and U87 cells were stably transfected with mCherry-EGFP-LC3B. Yellow fluorescence indicates the formation of autophagosomes while the red signal represents the acidic autophagolysosomes. Scale bar, 10 μm. (<bold>D</bold>) Quantitative analysis of the autophagosome accumulation effect of compound-7g-treated cells. Yellow dots were counted in three independent experiments shown in (<bold>D</bold>). The data are expressed as means ± SD (n = 3). * <italic>P</italic> < 0.05; ** <italic>P</italic> < 0.01; *** <italic>P</italic> < 0.001 compared with the control group.</p></caption><graphic xlink:href="molecules-24-02722-g004"></graphic></fig><fig id="molecules-24-02722-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>Compound-7g promoted accumulation of ubiquitinated proteins and ER stress because of induced autophagic flux blockage in LN229 and U87 cells. (<bold>A</bold>,<bold>B</bold>) Immunoblotting analysis for the ubiquitinated proteins and expression of ER stress related proteins in glioblastoma cells treated with the indicated concentrations of compound-7g. Tubulin was loaded as a control.</p></caption><graphic xlink:href="molecules-24-02722-g005"></graphic></fig></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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