Anti‐Metastatic Effect of Supercritical Extracts from the Citrus hassaku Pericarp via Inhibition of C‐X‐C Chemokine Receptor Type 4 (CXCR4) and Matrix Metalloproteinase‐9 (MMP‐9)
Identifieur interne : 001A75 ( Istex/Corpus ); précédent : 001A74; suivant : 001A76Anti‐Metastatic Effect of Supercritical Extracts from the Citrus hassaku Pericarp via Inhibition of C‐X‐C Chemokine Receptor Type 4 (CXCR4) and Matrix Metalloproteinase‐9 (MMP‐9)
Auteurs : Chulwon Kim ; Dongmin Kim ; Dongwoo Nam ; Won-Seok Chung ; Kyoo Seok Ahn ; Sung-Hoon Kim ; Seung-Hoon Choi ; Bum Sang Shim ; Somi K. Cho ; Kwang Seok AhnSource :
- Phytotherapy Research [ 0951-418X ] ; 2014-09.
Abstract
The fruit of hassaku (Citrus hassaku Hort. ex Tanaka) is locally known as phalsak in Korea. Recently, the fruit extract has been known to exhibit in vivo preventive effects against UVB‐induced pigmentation, antiallergic activity, and enhancement of blood fluidity. However, the exact mechanisms of how supercritical extracts of phalsak peel (SEPS) inhibits tumor metastasis and invasion are still not fully understood. We found that SEPS could downregulate the constitutive expression of both CXCR4 and HER2 in human breast cancer MDA‐MB‐231 cells as compared with other cells. SEPS also suppressed matrix metalloproteinase‐9 (MMP‐9) expression and its enzymatic activity under non‐cytotoxic concentrations. Neither proteasome inhibition nor lysosomal stabilization had any effect on the SEPS‐induced decrease in CXCR4 expression. A detailed study of the underlying molecular mechanisms revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by downregulation of mRNA expression, suppression of NF‐κB activity, and inhibition of chromatin immunoprecipitation activity. Suppression of CXCR4 expression by SEPS correlated with the inhibition of CXCL12‐stimulated invasion of MDA‐MB‐231 cells. Overall, our results indicate, for the first time, that SEPS can suppress CXCR4 and MMP‐9 expressions through blockade of NF‐κB activation and thus has the potential to suppress metastasis of breast cancer. Copyright © 2014 John Wiley & Sons, Ltd.
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DOI: 10.1002/ptr.5140
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Cho</name><affiliation><mods:affiliation>Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, 690‐756, Jeju, Republic of Korea</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Kwang Seok Ahn, Department of Korean Pathology, College of Korean Medicine, Kyung Hee University, 1 Hoegi‐Dong Dongdaemun‐Gu, Seoul 130‐701, Republic of Korea; Somi Kim Cho, Faculty of Biotechnology, Jeju National University, 66 Jejudaehakno, Jeju, 690‐756, Republic of Korea.E-mail: (Kwang Seok Ahn); (Somi Kim Cho)</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ksahn@khu.ac.krsomikim@jejunu.ac.kr</mods:affiliation></affiliation></author><author><name sortKey="Ahn, Kwang Seok" sort="Ahn, Kwang Seok" uniqKey="Ahn K" first="Kwang Seok" last="Ahn">Kwang Seok Ahn</name><affiliation><mods:affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Kwang Seok Ahn, Department of Korean Pathology, College of Korean Medicine, Kyung Hee University, 1 Hoegi‐Dong Dongdaemun‐Gu, Seoul 130‐701, Republic of Korea; Somi Kim Cho, Faculty of Biotechnology, Jeju National University, 66 Jejudaehakno, Jeju, 690‐756, Republic of Korea.E-mail: (Kwang Seok Ahn); (Somi Kim Cho)</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ksahn@khu.ac.krsomikim@jejunu.ac.kr</mods:affiliation></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">ISTEX</idno><idno type="RBID">ISTEX:AE838AADBC5F6B8ADEF36B734B03B32A6E8E3815</idno><date when="2014" year="2014">2014</date><idno type="doi">10.1002/ptr.5140</idno><idno type="url">https://api.istex.fr/ark:/67375/WNG-T4CZVXGK-D/fulltext.pdf</idno><idno type="wicri:Area/Istex/Corpus">001A75</idno><idno type="wicri:explorRef" wicri:stream="Istex" wicri:step="Corpus" wicri:corpus="ISTEX">001A75</idno></publicationStmt><sourceDesc><biblStruct><analytic><title level="a" type="main">Anti‐Metastatic Effect of Supercritical Extracts from the Citrus hassaku Pericarp via Inhibition of C‐X‐C Chemokine Receptor Type 4 (CXCR4) and Matrix Metalloproteinase‐9 (MMP‐9)</title><author><name sortKey="Kim, Chulwon" sort="Kim, Chulwon" uniqKey="Kim C" first="Chulwon" last="Kim">Chulwon Kim</name><affiliation><mods:affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</mods:affiliation></affiliation></author><author><name sortKey="Kim, Dongmin" sort="Kim, Dongmin" uniqKey="Kim D" first="Dongmin" last="Kim">Dongmin Kim</name><affiliation><mods:affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</mods:affiliation></affiliation></author><author><name sortKey="Nam, Dongwoo" sort="Nam, Dongwoo" uniqKey="Nam D" first="Dongwoo" last="Nam">Dongwoo Nam</name><affiliation><mods:affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</mods:affiliation></affiliation></author><author><name sortKey="Chung, Won Eok" sort="Chung, Won Eok" uniqKey="Chung W" first="Won-Seok" last="Chung">Won-Seok Chung</name><affiliation><mods:affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</mods:affiliation></affiliation></author><author><name sortKey="Ahn, Kyoo Seok" sort="Ahn, Kyoo Seok" uniqKey="Ahn K" first="Kyoo Seok" last="Ahn">Kyoo Seok Ahn</name><affiliation><mods:affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</mods:affiliation></affiliation></author><author><name sortKey="Kim, Sung Oon" sort="Kim, Sung Oon" uniqKey="Kim S" first="Sung-Hoon" last="Kim">Sung-Hoon Kim</name><affiliation><mods:affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</mods:affiliation></affiliation></author><author><name sortKey="Choi, Seung Oon" sort="Choi, Seung Oon" uniqKey="Choi S" first="Seung-Hoon" last="Choi">Seung-Hoon Choi</name><affiliation><mods:affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</mods:affiliation></affiliation></author><author><name sortKey="Shim, Bum Sang" sort="Shim, Bum Sang" uniqKey="Shim B" first="Bum Sang" last="Shim">Bum Sang Shim</name><affiliation><mods:affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</mods:affiliation></affiliation></author><author><name sortKey="Cho, Somi K" sort="Cho, Somi K" uniqKey="Cho S" first="Somi K." last="Cho">Somi K. Cho</name><affiliation><mods:affiliation>Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, 690‐756, Jeju, Republic of Korea</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Kwang Seok Ahn, Department of Korean Pathology, College of Korean Medicine, Kyung Hee University, 1 Hoegi‐Dong Dongdaemun‐Gu, Seoul 130‐701, Republic of Korea; Somi Kim Cho, Faculty of Biotechnology, Jeju National University, 66 Jejudaehakno, Jeju, 690‐756, Republic of Korea.E-mail: (Kwang Seok Ahn); (Somi Kim Cho)</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ksahn@khu.ac.krsomikim@jejunu.ac.kr</mods:affiliation></affiliation></author><author><name sortKey="Ahn, Kwang Seok" sort="Ahn, Kwang Seok" uniqKey="Ahn K" first="Kwang Seok" last="Ahn">Kwang Seok Ahn</name><affiliation><mods:affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</mods:affiliation></affiliation><affiliation><mods:affiliation>Correspondence to: Kwang Seok Ahn, Department of Korean Pathology, College of Korean Medicine, Kyung Hee University, 1 Hoegi‐Dong Dongdaemun‐Gu, Seoul 130‐701, Republic of Korea; Somi Kim Cho, Faculty of Biotechnology, Jeju National University, 66 Jejudaehakno, Jeju, 690‐756, Republic of Korea.E-mail: (Kwang Seok Ahn); (Somi Kim Cho)</mods:affiliation></affiliation><affiliation><mods:affiliation>E-mail: ksahn@khu.ac.krsomikim@jejunu.ac.kr</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">Phytotherapy Research</title><title level="j" type="alt">PHYTOTHERAPY RESEARCH</title><idno type="ISSN">0951-418X</idno><idno type="eISSN">1099-1573</idno><imprint><biblScope unit="vol">28</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1374">1374</biblScope><biblScope unit="page" to="1382">1382</biblScope><biblScope unit="page-count">9</biblScope><date type="published" when="2014-09">2014-09</date></imprint><idno type="ISSN">0951-418X</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0951-418X</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract">The fruit of hassaku (Citrus hassaku Hort. ex Tanaka) is locally known as phalsak in Korea. Recently, the fruit extract has been known to exhibit in vivo preventive effects against UVB‐induced pigmentation, antiallergic activity, and enhancement of blood fluidity. However, the exact mechanisms of how supercritical extracts of phalsak peel (SEPS) inhibits tumor metastasis and invasion are still not fully understood. We found that SEPS could downregulate the constitutive expression of both CXCR4 and HER2 in human breast cancer MDA‐MB‐231 cells as compared with other cells. SEPS also suppressed matrix metalloproteinase‐9 (MMP‐9) expression and its enzymatic activity under non‐cytotoxic concentrations. Neither proteasome inhibition nor lysosomal stabilization had any effect on the SEPS‐induced decrease in CXCR4 expression. A detailed study of the underlying molecular mechanisms revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by downregulation of mRNA expression, suppression of NF‐κB activity, and inhibition of chromatin immunoprecipitation activity. Suppression of CXCR4 expression by SEPS correlated with the inhibition of CXCL12‐stimulated invasion of MDA‐MB‐231 cells. Overall, our results indicate, for the first time, that SEPS can suppress CXCR4 and MMP‐9 expressions through blockade of NF‐κB activation and thus has the potential to suppress metastasis of breast cancer. Copyright © 2014 John Wiley & Sons, Ltd.</div></front></TEI><istex><corpusName>wiley</corpusName><keywords><teeft><json:string>sep</json:string><json:string>cxcr4</json:string><json:string>metastasis</json:string><json:string>receptor</json:string><json:string>downregulation</json:string><json:string>chemokine</json:string><json:string>actin</json:string><json:string>mrna</json:string><json:string>phytother</json:string><json:string>john wiley son</json:string><json:string>cxcr4 expression</json:string><json:string>hassaku</json:string><json:string>assay</json:string><json:string>breast cancer cell</json:string><json:string>constitutive</json:string><json:string>copyright</json:string><json:string>downregulate</json:string><json:string>breast cancer</json:string><json:string>tanaka</json:string><json:string>hepg2</json:string><json:string>independent experiment</json:string><json:string>citrus</json:string><json:string>western blot analysis</json:string><json:string>human breast cancer cell</json:string><json:string>constitutive activation</json:string><json:string>matrix</json:string><json:string>equal amount</json:string><json:string>matrix metalloproteinases</json:string><json:string>nuclear translocation</json:string><json:string>cxcr4 mrna</json:string><json:string>cancer metastasis</json:string><json:string>cxcr4 promoter</json:string><json:string>carcinoma</json:string><json:string>transwell chamber</json:string><json:string>basal medium</json:string><json:string>invasion assay</json:string><json:string>immunocytochemical analysis</json:string><json:string>same blot</json:string><json:string>first time</json:string><json:string>transcriptional level</json:string><json:string>degradation</json:string><json:string>flavanone glycoside</json:string><json:string>supercritical extract</json:string><json:string>thermo fisher scientific</json:string><json:string>wound healing assay</json:string><json:string>cell line</json:string><json:string>jeju national university</json:string><json:string>tumor cell</json:string><json:string>chemokine receptor</json:string><json:string>actin antibody</json:string><json:string>tumor metastasis</json:string><json:string>sep downregulated</json:string><json:string>downregulate cxcr4 expression</json:string><json:string>korean medicine</json:string><json:string>lysosomal degradation</json:string><json:string>immature fruit</json:string><json:string>chip assay</json:string><json:string>breast cancer metastasis</json:string><json:string>cancer cell</json:string><json:string>chemokine receptor cxcr4</json:string><json:string>biol chem</json:string><json:string>nuclear extract</json:string></teeft></keywords><author><json:item><name>Chulwon Kim</name><affiliations><json:string>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</json:string></affiliations></json:item><json:item><name>Dongmin Kim</name><affiliations><json:string>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</json:string></affiliations></json:item><json:item><name>Dongwoo Nam</name><affiliations><json:string>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</json:string></affiliations></json:item><json:item><name>Won‐Seok Chung</name><affiliations><json:string>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</json:string></affiliations></json:item><json:item><name>Kyoo Seok Ahn</name><affiliations><json:string>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</json:string></affiliations></json:item><json:item><name>Sung‐Hoon Kim</name><affiliations><json:string>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</json:string></affiliations></json:item><json:item><name>Seung‐Hoon Choi</name><affiliations><json:string>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</json:string></affiliations></json:item><json:item><name>Bum Sang Shim</name><affiliations><json:string>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</json:string></affiliations></json:item><json:item><name>Somi K. Cho</name><affiliations><json:string>Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, 690‐756, Jeju, Republic of Korea</json:string><json:string>Correspondence to: Kwang Seok Ahn, Department of Korean Pathology, College of Korean Medicine, Kyung Hee University, 1 Hoegi‐Dong Dongdaemun‐Gu, Seoul 130‐701, Republic of Korea; Somi Kim Cho, Faculty of Biotechnology, Jeju National University, 66 Jejudaehakno, Jeju, 690‐756, Republic of Korea.E-mail: (Kwang Seok Ahn); (Somi Kim Cho)</json:string><json:string>E-mail: ksahn@khu.ac.krsomikim@jejunu.ac.kr</json:string></affiliations></json:item><json:item><name>Kwang Seok Ahn</name><affiliations><json:string>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</json:string><json:string>Correspondence to: Kwang Seok Ahn, Department of Korean Pathology, College of Korean Medicine, Kyung Hee University, 1 Hoegi‐Dong Dongdaemun‐Gu, Seoul 130‐701, Republic of Korea; Somi Kim Cho, Faculty of Biotechnology, Jeju National University, 66 Jejudaehakno, Jeju, 690‐756, Republic of Korea.E-mail: (Kwang Seok Ahn); (Somi Kim Cho)</json:string><json:string>E-mail: ksahn@khu.ac.krsomikim@jejunu.ac.kr</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>Citrus hassaku Hort. ex Tanaka</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CXCR4</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>MMP‐9</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>NF‐κB</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>metastasis</value></json:item></subject><articleId><json:string>PTR5140</json:string></articleId><arkIstex>ark:/67375/WNG-T4CZVXGK-D</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>article</json:string></originalGenre><abstract>The fruit of hassaku (Citrus hassaku Hort. ex Tanaka) is locally known as phalsak in Korea. Recently, the fruit extract has been known to exhibit in vivo preventive effects against UVB‐induced pigmentation, antiallergic activity, and enhancement of blood fluidity. However, the exact mechanisms of how supercritical extracts of phalsak peel (SEPS) inhibits tumor metastasis and invasion are still not fully understood. We found that SEPS could downregulate the constitutive expression of both CXCR4 and HER2 in human breast cancer MDA‐MB‐231 cells as compared with other cells. SEPS also suppressed matrix metalloproteinase‐9 (MMP‐9) expression and its enzymatic activity under non‐cytotoxic concentrations. Neither proteasome inhibition nor lysosomal stabilization had any effect on the SEPS‐induced decrease in CXCR4 expression. A detailed study of the underlying molecular mechanisms revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by downregulation of mRNA expression, suppression of NF‐κB activity, and inhibition of chromatin immunoprecipitation activity. Suppression of CXCR4 expression by SEPS correlated with the inhibition of CXCL12‐stimulated invasion of MDA‐MB‐231 cells. Overall, our results indicate, for the first time, that SEPS can suppress CXCR4 and MMP‐9 expressions through blockade of NF‐κB activation and thus has the potential to suppress metastasis of breast cancer. 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CANCER</title><author xml:id="author-0000"><persName><forename type="first">Chulwon</forename><surname>Kim</surname></persName><affiliation><orgName type="division">College of Korean Medicine and Institute of Korean Medicine</orgName><orgName type="institution">Kyung Hee University</orgName><address><street>1 Hoegidong Dongdaemungu</street><settlement>Seoul</settlement><postCode>130‐701</postCode><country key="KR" xml:lang="en">KOREA, REPUBLIC OF</country></address></affiliation></author><author xml:id="author-0001"><persName><forename type="first">Dongmin</forename><surname>Kim</surname></persName><affiliation><orgName type="division">College of Korean Medicine and Institute of Korean Medicine</orgName><orgName type="institution">Kyung Hee University</orgName><address><street>1 Hoegidong Dongdaemungu</street><settlement>Seoul</settlement><postCode>130‐701</postCode><country key="KR" xml:lang="en">KOREA, REPUBLIC OF</country></address></affiliation></author><author 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<lineatedText><line>Correspondence to: Kwang Seok Ahn, Department of Korean Pathology, College of Korean Medicine, Kyung Hee University, 1 Hoegi‐Dong Dongdaemun‐Gu, Seoul 130‐701, Republic of Korea; Somi Kim Cho, Faculty of Biotechnology, Jeju National University, 66 Jejudaehakno, Jeju, 690‐756, Republic of Korea.</line><line>E-mail: <email>ksahn@khu.ac.kr</email> (Kwang Seok Ahn); <email>somikim@jejunu.ac.kr</email> (Somi Kim Cho)</line></lineatedText></correspondenceTo><selfCitationGroup><citation type="self" xml:id="ptr5140-cit-0000"><author><familyName>Kim</familyName>
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<givenNames>K. S.</givenNames></author> (<pubYear year="2014">2014</pubYear>), <articleTitle>Anti‐Metastatic Effect of Supercritical Extracts from the <i>Citrus hassaku</i> Pericarp via Inhibition of C‐X‐C Chemokine Receptor Type 4 (CXCR4) and Matrix Metalloproteinase‐9 (MMP‐9)</articleTitle>, <journalTitle>Phytother. Res.</journalTitle>, <vol>28</vol>, <pageFirst>1374</pageFirst>–<pageLast>1382</pageLast>. doi: <accessionId ref="info:doi/10.1002/ptr.5140">10.1002/ptr.5140</accessionId></citation></selfCitationGroup><linkGroup><link type="toTypesetVersion" href="file:PTR.PTR5140.pdf"></link></linkGroup></publicationMeta><contentMeta><titleGroup><title type="main">Anti‐Metastatic Effect of Supercritical Extracts from the <i>Citrus hassaku</i> Pericarp via Inhibition of C‐X‐C Chemokine Receptor Type 4 (CXCR4) and Matrix Metalloproteinase‐9 (MMP‐9)</title><title type="short">SEPS INHIBITS METASTASIS OF BREAST CANCER</title><title type="shortAuthors">C. KIM <i>ET AL</i>.</title></titleGroup><creators><creator creatorRole="author" xml:id="ptr5140-cr-0001" affiliationRef="#ptr5140-aff-0001" noteRef="#ptr5140-note-0001"><personName><givenNames>Chulwon</givenNames><familyName>Kim</familyName></personName></creator><creator creatorRole="author" xml:id="ptr5140-cr-0002" affiliationRef="#ptr5140-aff-0001" noteRef="#ptr5140-note-0001"><personName><givenNames>Dongmin</givenNames><familyName>Kim</familyName></personName></creator><creator creatorRole="author" xml:id="ptr5140-cr-0003" affiliationRef="#ptr5140-aff-0001"><personName><givenNames>Dongwoo</givenNames><familyName>Nam</familyName></personName></creator><creator creatorRole="author" xml:id="ptr5140-cr-0004" affiliationRef="#ptr5140-aff-0001"><personName><givenNames>Won‐Seok</givenNames><familyName>Chung</familyName></personName></creator><creator creatorRole="author" xml:id="ptr5140-cr-0005" affiliationRef="#ptr5140-aff-0001"><personName><givenNames>Kyoo Seok</givenNames><familyName>Ahn</familyName></personName></creator><creator creatorRole="author" xml:id="ptr5140-cr-0006" affiliationRef="#ptr5140-aff-0001"><personName><givenNames>Sung‐Hoon</givenNames><familyName>Kim</familyName></personName></creator><creator creatorRole="author" xml:id="ptr5140-cr-0007" affiliationRef="#ptr5140-aff-0001"><personName><givenNames>Seung‐Hoon</givenNames><familyName>Choi</familyName></personName></creator><creator creatorRole="author" xml:id="ptr5140-cr-0008" affiliationRef="#ptr5140-aff-0001"><personName><givenNames>Bum Sang</givenNames><familyName>Shim</familyName></personName></creator><creator creatorRole="author" xml:id="ptr5140-cr-0009" affiliationRef="#ptr5140-aff-0002" corresponding="yes"><personName><givenNames>Somi K.</givenNames><familyName>Cho</familyName></personName></creator><creator creatorRole="author" xml:id="ptr5140-cr-0010" affiliationRef="#ptr5140-aff-0001" corresponding="yes"><personName><givenNames>Kwang Seok</givenNames><familyName>Ahn</familyName></personName></creator></creators><affiliationGroup><affiliation countryCode="KR" type="organization" xml:id="ptr5140-aff-0001"><orgDiv>College of Korean Medicine and Institute of Korean Medicine</orgDiv><orgName>Kyung Hee University</orgName><address><street>1 Hoegidong Dongdaemungu</street><city>Seoul</city><postCode>130‐701</postCode><country>Republic of Korea</country></address></affiliation><affiliation countryCode="KR" type="organization" xml:id="ptr5140-aff-0002"><orgDiv>Faculty of Biotechnology, College of Applied Life Sciences</orgDiv><orgName>Jeju National University</orgName><address><city>Jeju</city><postCode>690‐756</postCode><country>Republic of Korea</country></address></affiliation></affiliationGroup><keywordGroup type="author"><keyword xml:id="ptr5140-kwd-0001"><i>Citrus hassaku</i> Hort. ex Tanaka</keyword><keyword xml:id="ptr5140-kwd-0002">CXCR4</keyword><keyword xml:id="ptr5140-kwd-0003">MMP‐9</keyword><keyword xml:id="ptr5140-kwd-0004">NF‐κB</keyword><keyword xml:id="ptr5140-kwd-0005">metastasis</keyword></keywordGroup><fundingInfo><fundingAgency>Korea Science and Engineering Foundation (KOSEF)</fundingAgency><fundingNumber>2011‐0006220</fundingNumber></fundingInfo><fundingInfo><fundingAgency>Technology Development Program for Agriculture and Forestry (2010), Ministry for Food, Agriculture, Forestry, and Fisheries, Republic of Korea</fundingAgency></fundingInfo><abstractGroup><abstract type="main"><p>The fruit of hassaku (<i>Citrus hassaku</i> Hort. ex Tanaka) is locally known as phalsak in Korea. Recently, the fruit extract has been known to exhibit <i>in vivo</i> preventive effects against UVB‐induced pigmentation, antiallergic activity, and enhancement of blood fluidity. However, the exact mechanisms of how supercritical extracts of phalsak peel (SEPS) inhibits tumor metastasis and invasion are still not fully understood. We found that SEPS could downregulate the constitutive expression of both CXCR4 and HER2 in human breast cancer MDA‐MB‐231 cells as compared with other cells. SEPS also suppressed matrix metalloproteinase‐9 (MMP‐9) expression and its enzymatic activity under non‐cytotoxic concentrations. Neither proteasome inhibition nor lysosomal stabilization had any effect on the SEPS‐induced decrease in CXCR4 expression. A detailed study of the underlying molecular mechanisms revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by downregulation of mRNA expression, suppression of NF‐κB activity, and inhibition of chromatin immunoprecipitation activity. Suppression of CXCR4 expression by SEPS correlated with the inhibition of CXCL12‐stimulated invasion of MDA‐MB‐231 cells. Overall, our results indicate, for the first time, that SEPS can suppress CXCR4 and MMP‐9 expressions through blockade of NF‐κB activation and thus has the potential to suppress metastasis of breast cancer. Copyright © 2014 John Wiley & Sons, Ltd.</p></abstract></abstractGroup></contentMeta><noteGroup><note xml:id="ptr5140-note-0001"><p>These authors equally contributed to this work.</p></note></noteGroup></header></component></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Anti‐Metastatic Effect of Supercritical Extracts from the Citrus hassaku Pericarp via Inhibition of C‐X‐C Chemokine Receptor Type 4 (CXCR4) and Matrix Metalloproteinase‐9 (MMP‐9)</title></titleInfo><titleInfo type="abbreviated" lang="en"><title>SEPS INHIBITS METASTASIS OF BREAST CANCER</title></titleInfo><titleInfo type="alternative" contentType="CDATA" lang="en"><title>Anti‐Metastatic Effect of Supercritical Extracts from the Citrus hassaku Pericarp via Inhibition of C‐X‐C Chemokine Receptor Type 4 (CXCR4) and Matrix Metalloproteinase‐9 (MMP‐9)</title></titleInfo><name type="personal"><namePart type="given">Chulwon</namePart><namePart type="family">Kim</namePart><affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</affiliation><description>These authors equally contributed to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dongmin</namePart><namePart type="family">Kim</namePart><affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</affiliation><description>These authors equally contributed to this work.</description><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dongwoo</namePart><namePart type="family">Nam</namePart><affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Won‐Seok</namePart><namePart type="family">Chung</namePart><affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kyoo Seok</namePart><namePart type="family">Ahn</namePart><affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Sung‐Hoon</namePart><namePart type="family">Kim</namePart><affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Seung‐Hoon</namePart><namePart type="family">Choi</namePart><affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Bum Sang</namePart><namePart type="family">Shim</namePart><affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Somi K.</namePart><namePart type="family">Cho</namePart><affiliation>Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, 690‐756, Jeju, Republic of Korea</affiliation><affiliation>Correspondence to: Kwang Seok Ahn, Department of Korean Pathology, College of Korean Medicine, Kyung Hee University, 1 Hoegi‐Dong Dongdaemun‐Gu, Seoul 130‐701, Republic of Korea; Somi Kim Cho, Faculty of Biotechnology, Jeju National University, 66 Jejudaehakno, Jeju, 690‐756, Republic of Korea.E-mail: (Kwang Seok Ahn); (Somi Kim Cho)</affiliation><affiliation>E-mail: ksahn@khu.ac.krsomikim@jejunu.ac.kr</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kwang Seok</namePart><namePart type="family">Ahn</namePart><affiliation>College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, 1 Hoegidong Dongdaemungu, 130‐701, Seoul, Republic of Korea</affiliation><affiliation>Correspondence to: Kwang Seok Ahn, Department of Korean Pathology, College of Korean Medicine, Kyung Hee University, 1 Hoegi‐Dong Dongdaemun‐Gu, Seoul 130‐701, Republic of Korea; Somi Kim Cho, Faculty of Biotechnology, Jeju National University, 66 Jejudaehakno, Jeju, 690‐756, Republic of Korea.E-mail: (Kwang Seok Ahn); (Somi Kim Cho)</affiliation><affiliation>E-mail: ksahn@khu.ac.krsomikim@jejunu.ac.kr</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="article" displayLabel="article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</genre><originInfo><publisher>Blackwell Publishing Ltd</publisher><dateIssued encoding="w3cdtf">2014-09</dateIssued><dateCreated encoding="w3cdtf">2014-02-25</dateCreated><dateCaptured encoding="w3cdtf">2013-11-20</dateCaptured><dateValid encoding="w3cdtf">2014-02-10</dateValid><edition>Kim C., Kim D., Nam D., Chung W.‐S., Ahn K. S., Kim S.‐H., Choi S.‐H., Shim B. S., Cho S. K., and Ahn K. S. (2014), Anti‐Metastatic Effect of Supercritical Extracts from the Citrus hassaku Pericarp via Inhibition of C‐X‐C Chemokine Receptor Type 4 (CXCR4) and Matrix Metalloproteinase‐9 (MMP‐9), Phytother. Res., 28, 1374–1382. doi: 10.1002/ptr.5140</edition><copyrightDate encoding="w3cdtf">2014</copyrightDate></originInfo><language><languageTerm type="code" authority="rfc3066">en</languageTerm><languageTerm type="code" authority="iso639-2b">eng</languageTerm></language><abstract>The fruit of hassaku (Citrus hassaku Hort. ex Tanaka) is locally known as phalsak in Korea. Recently, the fruit extract has been known to exhibit in vivo preventive effects against UVB‐induced pigmentation, antiallergic activity, and enhancement of blood fluidity. However, the exact mechanisms of how supercritical extracts of phalsak peel (SEPS) inhibits tumor metastasis and invasion are still not fully understood. We found that SEPS could downregulate the constitutive expression of both CXCR4 and HER2 in human breast cancer MDA‐MB‐231 cells as compared with other cells. SEPS also suppressed matrix metalloproteinase‐9 (MMP‐9) expression and its enzymatic activity under non‐cytotoxic concentrations. Neither proteasome inhibition nor lysosomal stabilization had any effect on the SEPS‐induced decrease in CXCR4 expression. A detailed study of the underlying molecular mechanisms revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by downregulation of mRNA expression, suppression of NF‐κB activity, and inhibition of chromatin immunoprecipitation activity. Suppression of CXCR4 expression by SEPS correlated with the inhibition of CXCL12‐stimulated invasion of MDA‐MB‐231 cells. 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