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Discovery of Aurovertin B as a Potent Metastasis Inhibitor against Triple-Negative Breast Cancer: Elucidating the Complex Role of the ATF3-DUSP1 Axis | Journal of Pharmacology and Experimental Therapeutics
<!DOCTYPE html> <html lang="en" dir="ltr" xmlns="http://www.w3.org/1999/xhtml" xmlns:mml="http://www.w3.org/1998/Math/MathML"> <head prefix="og: http://ogp.me/ns# article: http://ogp.me/ns/article# book: http://ogp.me/ns/book#" > <!--[if IE]><![endif]--> <link rel="dns-prefetch" href="//securepubads.g.doubleclick.net" /> <link rel="dns-prefetch" href="//cdn.jsdelivr.net" /> <link rel="dns-prefetch" href="//www.google.com" /> <link rel="dns-prefetch" href="//www.googletagmanager.com" /> <link rel="dns-prefetch" href="//cdn.foxycart.com" /> <link rel="dns-prefetch" href="//scholar.google.com" /> <meta http-equiv="Content-Type" content="text/html; charset=utf-8" /> <meta name="Generator" content="Drupal 7 (http://drupal.org)" /> <link rel="canonical" href="https://jpet.aspetjournals.org/content/early/2024/06/07/jpet.124.002264" /> <link rel="alternate" type="application/pdf" title="Full Text (PDF)" href="/content/early/2024/06/07/jpet.124.002264.full.pdf" /> <meta name="type" content="article" /> <meta name="category" content="other" /> <meta name="HW.identifier" content="/jpet/early/2024/06/07/jpet.124.002264.atom" /> <meta name="HW.pisa" content="jpet;jpet.124.002264v1" /> <meta name="DC.Format" content="text/html" /> <meta name="DC.Language" content="en" /> <meta name="DC.Title" content="Discovery of Aurovertin B as a Potent Metastasis Inhibitor against Triple-Negative Breast Cancer: Elucidating the Complex Role of the ATF3-DUSP1 Axis" /> <meta name="DC.Identifier" content="10.1124/jpet.124.002264" /> <meta name="DC.Date" content="2024-06-07" /> <meta name="DC.Publisher" content="American Society for Pharmacology and Experimental Therapeutics" /> <meta name="DC.AccessRights" content="restricted" /> <meta name="DC.Description" content="Triple-negative breast cancer (TNBC) is characterized by high mortality rates primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937 and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of DUSP1 (dual-specificity phosphatase 1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified ATF3 (activating transcription factor 3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the molecular mechanisms driving metastasis in TNBC. Significance Statement We construct a high-throughput phenotypic screening system utilizing EMT marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis." /> <meta name="DC.Contributor" content="Jian-Jun Shen" /> <meta name="DC.Contributor" content="Xi Yang" /> <meta name="DC.Contributor" content="Meng Yu" /> <meta name="DC.Contributor" content="Qing-Cui Li" /> <meta name="DC.Contributor" content="Ru-Yu Wang" /> <meta name="DC.Contributor" content="Wen-Yan Yu" /> <meta name="DC.Contributor" content="Jia-Li Zhang" /> <meta name="DC.Contributor" content="Yi-Li Chen" /> <meta name="DC.Contributor" content="Wen-Ting Zhu" /> <meta name="DC.Contributor" content="Jia Li" /> <meta name="DC.Contributor" content="Zha-Jun Zhan" /> <meta name="DC.Contributor" content="Rui Wu" /> <meta name="article:published_time" content="2024-01-01" /> <meta name="article:section" content="Drug Discovery and Translational Medicine" /> <meta name="citation_title" content="Discovery of Aurovertin B as a Potent Metastasis Inhibitor against Triple-Negative Breast Cancer: Elucidating the Complex Role of the ATF3-DUSP1 Axis" /> <meta name="citation_abstract" lang="en" content="<p>Triple-negative breast cancer (TNBC) is characterized by high mortality rates primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937 and 4T1. Also, its remarkable antimetastatic activity was demonstrated <i>in vivo</i> via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of DUSP1 (dual-specificity phosphatase 1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified ATF3 (activating transcription factor 3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the molecular mechanisms driving metastasis in TNBC.</p><p><b>Significance Statement</b> We construct a high-throughput phenotypic screening system utilizing EMT marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via <i>in vivo</i> and <i>in vitro</i> experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis.</p>" /> <meta name="citation_journal_title" content="Journal of Pharmacology and Experimental Therapeutics" /> <meta name="citation_publisher" content="American Society for Pharmacology and Experimental Therapeutics" /> <meta name="citation_publication_date" content="2024/01/01" /> <meta name="citation_mjid" content="jpet;jpet.124.002264v1" /> <meta name="citation_id" content="jpet.124.002264v1" /> <meta name="citation_public_url" content="https://jpet.aspetjournals.org/content/early/2024/06/07/jpet.124.002264" /> <meta name="citation_abstract_html_url" content="https://jpet.aspetjournals.org/content/early/2024/06/07/jpet.124.002264.abstract" /> <meta name="citation_full_html_url" content="https://jpet.aspetjournals.org/content/early/2024/06/07/jpet.124.002264.full" /> <meta name="citation_pdf_url" content="https://jpet.aspetjournals.org/content/jpet/early/2024/06/07/jpet.124.002264.full.pdf" /> <meta name="citation_issn" content="0022-3565" /> <meta name="citation_issn" content="1521-0103" /> <meta name="citation_journal_abbrev" content="J Pharmacol Exp Ther" /> <meta name="citation_doi" content="10.1124/jpet.124.002264" /> <meta name="citation_pmid" content="38849141" /> <meta name="citation_num_pages" content="35" /> <meta name="citation_article_type" content="Other" /> <meta name="citation_section" content="Drug Discovery and Translational Medicine" /> <meta name="citation_author" content="Jian-Jun Shen" /> <meta name="citation_author_institution" content="College of Pharmaceutical Science, Zhejiang University of Technology, China" /> <meta name="citation_author" content="Xi Yang" /> <meta name="citation_author_institution" content="College of Pharmaceutical Science, Zhejiang University of Technology, China" /> <meta name="citation_author" content="Meng Yu" /> <meta name="citation_author_institution" content="School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, China" /> <meta name="citation_author" content="Qing-Cui Li" /> <meta name="citation_author_institution" content="School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, China" /> <meta name="citation_author" content="Ru-Yu Wang" /> <meta name="citation_author_institution" content="School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, China" /> <meta name="citation_author" content="Wen-Yan Yu" /> <meta name="citation_author_institution" content="College of Pharmaceutical Science, Zhejiang University of Technology, China" /> <meta name="citation_author" content="Jia-Li Zhang" /> <meta name="citation_author_institution" content="Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, China" /> <meta name="citation_author" content="Yi-Li Chen" /> <meta name="citation_author_institution" content="College of Pharmaceutical Science, Zhejiang University of Technology, China" /> <meta name="citation_author" content="Wen-Ting Zhu" /> <meta name="citation_author_institution" content="School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, China" /> <meta name="citation_author" content="Jia Li" /> <meta name="citation_author_institution" content="School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, China" /> <meta name="citation_author" content="Zha-Jun Zhan" /> <meta name="citation_author_institution" content="College of Pharmaceutical Science, Zhejiang University of Technology, China" /> <meta name="citation_author_email" content="wurui@ucas.ac.cn" /> <meta name="citation_author" content="Rui Wu" /> <meta name="citation_author_institution" content="School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, China" /> <meta name="citation_author_email" content="wurui@ucas.ac.cn" /> <meta name="citation_author_orcid" content="https://orcid.org/0000-0001-7229-2047" /> <meta name="twitter:title" content="Discovery of Aurovertin B as a Potent Metastasis Inhibitor against Triple-Negative Breast Cancer: Elucidating the Complex Role of the ATF3-DUSP1 Axis" /> <meta name="twitter:card" content="summary" /> <meta name="twitter:description" content="Triple-negative breast cancer (TNBC) is characterized by high mortality rates primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937 and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of DUSP1 (dual-specificity phosphatase 1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified ATF3 (activating transcription factor 3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the molecular mechanisms driving metastasis in TNBC. Significance Statement We construct a high-throughput phenotypic screening system utilizing EMT marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis." /> <meta name="og-title" property="og:title" content="Discovery of Aurovertin B as a Potent Metastasis Inhibitor against Triple-Negative Breast Cancer: Elucidating the Complex Role of the ATF3-DUSP1 Axis" /> <meta name="og-url" property="og:url" content="https://jpet.aspetjournals.org/content/early/2024/06/07/jpet.124.002264" /> <meta name="og-site-name" property="og:site_name" content="Journal of Pharmacology and Experimental Therapeutics" /> <meta name="og-description" property="og:description" content="Triple-negative breast cancer (TNBC) is characterized by high mortality rates primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937 and 4T1. Also, its remarkable antimetastatic activity was demonstrated in vivo via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of DUSP1 (dual-specificity phosphatase 1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified ATF3 (activating transcription factor 3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the molecular mechanisms driving metastasis in TNBC. Significance Statement We construct a high-throughput phenotypic screening system utilizing EMT marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via in vivo and in vitro experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis." /> <meta name="og-type" property="og:type" content="article" /> <meta name="og-image" property="og:image" content="" /> <link rel="shortlink" href="/node/155965" /> <link rel="shortcut icon" href="https://jpet.aspetjournals.org/sites/default/files/images/favicon.ico" type="image/vnd.microsoft.icon" /> <meta name="viewport" content="width=device-width, initial-scale=1" /> <title>Discovery of Aurovertin B as a Potent Metastasis Inhibitor against Triple-Negative Breast Cancer: Elucidating the Complex Role of the ATF3-DUSP1 Axis | Journal of Pharmacology and Experimental Therapeutics</title> <link type="text/css" rel="stylesheet" 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class="highwire-cite-metadata-article-type highwire-cite-metadata">Other</span><span class="separator-pipe"></span><span class="highwire-cite-metadata-art-cat highwire-cite-metadata"><span class="wrapper">Drug Discovery and Translational Medicine</span></span></div> <div class="highwire-cite-access"><span class="highwire-citation-access highwire-citation-access-check" data-pisa-id="jpet;jpet.124.002264" data-atom-uri="/jpet/early/2024/06/07/jpet.124.002264.atom" data-request-view="full"></span></div> <h1 class="highwire-cite-title" id="page-title"><strong>Discovery of Aurovertin B as a Potent Metastasis Inhibitor against Triple-Negative Breast Cancer: Elucidating the Complex Role of the ATF3-DUSP1 Axis</strong></h1> <div class="highwire-cite-authors"><div class="highwire-citation-authors-type highwire-citation-authors-type-author"><span class="contributor-of-type"><em></em></span> <span class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0">Jian-Jun Shen</span>, <span class="highwire-citation-author" data-delta="1">Xi Yang</span>, <span class="highwire-citation-author" data-delta="2">Meng Yu</span>, <span class="highwire-citation-author" data-delta="3">Qing-Cui Li</span>, <span class="highwire-citation-author" data-delta="4">Ru-Yu Wang</span>, <span class="highwire-citation-author" data-delta="5">Wen-Yan Yu</span>, <span class="highwire-citation-author" data-delta="6">Jia-Li Zhang</span>, <span class="highwire-citation-author" data-delta="7">Yi-Li Chen</span>, <span class="highwire-citation-author" data-delta="8">Wen-Ting Zhu</span>, <span class="highwire-citation-author" data-delta="9">Jia Li</span>, <span class="highwire-citation-author" data-delta="10">Zha-Jun Zhan</span> and <span class="highwire-citation-author" data-delta="11">Rui Wu</span></span></div></div> <div class="highwire-cite-metadata"><span class="highwire-cite-metadata-journal highwire-cite-metadata">Journal of Pharmacology and Experimental Therapeutics </span><span class="highwire-cite-metadata-date highwire-cite-metadata">June 7, 2024, </span><span class="highwire-cite-metadata-pages highwire-cite-metadata">JPET-AR-2024-002264; </span><span class="highwire-cite-metadata-doi highwire-cite-metadata">DOI: https://doi.org/10.1124/jpet.124.002264 </span></div> </div> <div id="hw-article-author-popups-top-node-155965--2898101555" style="display: none;"><div class="author-tooltip-0"><div class="author-tooltip-name">Jian-Jun Shen </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>College of Pharmaceutical Science, Zhejiang University of Technology, China</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Jian-Jun%2BShen%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=Shen%20J&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AJian-Jun%2BShen%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-1"><div class="author-tooltip-name">Xi Yang </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>College of Pharmaceutical Science, Zhejiang University of Technology, China</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Xi%2BYang%2B" target="_blank" class="" data-icon-position="" 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class="article abstract-view "><span class="highwire-journal-article-marker-start"></span><div class="section abstract" id="abstract-1"><h2>Abstract</h2><p id="p-1">Triple-negative breast cancer (TNBC) is characterized by high mortality rates primarily due to its propensity for metastasis. Addressing this challenge necessitates the development of effective antimetastatic therapies. This study aimed to identify natural compounds with potential antimetastatic properties mainly based on the high-throughput phenotypic screening system. This system, utilizing luciferase reporter gene assays combined with scratch wound assays, evaluates compounds based on their influence on the epithelial-mesenchymal transition (EMT) marker E-cadherin. Through this approach, aurovertin B (AVB) was revealed to have significant antimetastatic capability. Notably, AVB exhibited substantial metastasis suppression in many TNBC cell lines, including MDA-MB-231, HCC1937 and 4T1. Also, its remarkable antimetastatic activity was demonstrated <em>in vivo</em> via the orthotopic breast cancer mouse model. Further exploration revealed a pronounced association between AVB-induced upregulation of DUSP1 (dual-specificity phosphatase 1) and its inhibitory effect on TNBC metastasis. Additionally, microarray analysis conducted to elucidate the underlying mechanism of the AVB-DUSP1 interaction identified ATF3 (activating transcription factor 3) as a critical transcription factor instrumental in DUSP1 transcriptional activation. This discovery, coupled with observations of enhanced ATF3-DUSP1 expression and consequent reduction in TNBC metastatic foci in response to AVB, provides novel insights into the molecular mechanisms driving metastasis in TNBC.</p><p id="p-2"> <strong>Significance Statement</strong> We construct a high-throughput phenotypic screening system utilizing EMT marker E-cadherin promoter luciferase reporter gene combined with scratch wound assays. Aurovertin B was revealed to possess significant antimetastatic activity through this approach, which was further demonstrated via <em>in vivo</em> and <em>in vitro</em> experiments. The discovery of the regulatory role of the ATF3-DUSP1 pathway enriches our understanding of TNBC metastasis mechanism and suggests the potential of ATF3 and DUSP1 as biomarkers for diagnosing TNBC metastasis.</p></div><ul class="kwd-group"><li class="kwd"><a href="/keyword/cell-migration" class="hw-term hw-article-keyword hw-article-keyword-cell-migration" rel="nofollow">Cell migration</a></li><li class="kwd"><a href="/keyword/metastasis" class="hw-term hw-article-keyword hw-article-keyword-metastasis" rel="nofollow">Metastasis</a></li></ul><span class="highwire-journal-article-marker-end"></span></div><span class="related-urls"></span></div></div> </div> </div> </div> </div> </div> </div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-node-pager" > <div class="pane-content"> <div class="pager highwire-pager pager-mini clearfix highwire-node-pager highwire-article-pager"><span class="pager-prev"><a 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alt="Journal of Pharmacology and Experimental Therapeutics: 391 (3)" /></a></div> <div class="highwire-cite-col"> <a href="/content/391/3" class="highwire-cite-linked-title" data-icon-position="" data-hide-link-title="0"><span class="highwire-cite-title">Journal of Pharmacology and Experimental Therapeutics</span></a> <div class="highwire-cite-metadata"><span class="highwire-cite-metadata-volume highwire-cite-metadata">Vol. 391</span>, <span class="highwire-cite-metadata-issue highwire-cite-metadata">Issue 3 </span><div class="highwire-cite-metadata-pubdate highwire-cite-metadata">1 Dec 2024 </div></div> <div class="highwire-cite-extras"><div class='highwire-article-citation-variant-list'><ul class="links variants-list"><li class="toc first"><a href="/content/391/3.toc" class="highwire-variant-link variant-toc " title="Table of Contents" rel="alternate" type="text/html" data-icon-position="" data-hide-link-title="0">Table of Contents</a></li><li class="tocpdf"><a 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