Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation
Out of the breast cancer subtypes, triple-negative breast cancer (TNBC) has the poorest prognosis without effective targeted therapies. Metformin, a first-line drug for type 2 diabetes mellitus, was demonstrated to target breast cancer stem cells selectively. However, the efficiency and the mechanis...
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| Veröffentlicht in: | Cell discovery 2017-04, Vol.3 (1), p.17010-17010, Article 17010 |
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| creator | Shi, Peiguo Liu, Wenjing Tala Wang, Haixia Li, Fubing Zhang, Hailin Wu, Yingying Kong, Yanjie Zhou, Zhongmei Wang, Chunyan Chen, Wenlin Liu, Rong Chen, Ceshi |
| description | Out of the breast cancer subtypes, triple-negative breast cancer (TNBC) has the poorest prognosis without effective targeted therapies. Metformin, a first-line drug for type 2 diabetes mellitus, was demonstrated to target breast cancer stem cells selectively. However, the efficiency and the mechanism of action of metformin in TNBC are unclear. In this study, we demonstrated that metformin decreased the percentage of TNBC stem cells partially through the downregulation of the expression of the stem cell transcription factor Krüppel-like factor 5 (KLF5) and its downstream target genes, such as
Nanog
and
FGF-BP1
, in TNBC cell lines. Metformin induced glycogen synthase kinase-3β (GSK3β)-mediated KLF5 protein phosphorylation and degradation through the inhibition of protein kinase A (PKA) activity in TNBC cells. Consistently, PKA activators increased the expression levels of KLF5. We observed a positive correlation between p-CREB, p-GSK3β, KLF5 and FGF-BP1 protein levels in human TNBC samples. These findings suggest that metformin suppresses TNBC stem cells partially through the PKA-GSK3β-KLF5 signaling pathway. |
| doi_str_mv | 10.1038/celldisc.2017.10 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5396048</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>4321805993</sourcerecordid><originalsourceid>FETCH-LOGICAL-c532t-7bf356daf9add21662038f07ab944a1ee4eb0ca1dd0221c386912ae5d2e0fe133</originalsourceid><addsrcrecordid>eNp1kUFv1DAQhS0EotXSOydkiQuXlLETe-0LEqpaQCziAmfLsSchVeIE26nUf4-jbasFiZOtmW_e-PkR8prBJYNavXc4jn5I7pID25fSM3LOQchKaKmen9zPyEVKtwDABFdKiZfkjKtGAQh2Tsw3zN0cpyHQtC5LxJQw0RyHZcQqYG_zcIe0jWhTps4Gh5GmjBPdtifa3tNsY495CD39ergRtIhRj320vozO4RV50dkx4cXDuSM_b65_XH2uDt8_fbn6eKicqHmu9m1XC-ltp633nEnJi8MO9rbVTWMZYoMtOMu8B86Zq5XUjFsUniN0yOp6Rz4cdZe1ndA7DDna0SxxmGy8N7MdzN-dMPwy_XxnRK0lNKoIvHsQiPPvFVM2U_nbYtIGnNdkmNKyYVzDtuvtP-jtvMZQ7BVK6VoIqZtCwZFycU4pYvf0GAZmC9A8Bmi2ALfSjrw5NfE08BhXAdgRSKUVeownm_8n-gdFEKsW</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1889355694</pqid></control><display><type>article</type><title>Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation</title><source>DOAJ Directory of Open Access Journals</source><source>Springer Nature OA Free Journals</source><source>Nature Free</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Shi, Peiguo ; Liu, Wenjing ; Tala ; Wang, Haixia ; Li, Fubing ; Zhang, Hailin ; Wu, Yingying ; Kong, Yanjie ; Zhou, Zhongmei ; Wang, Chunyan ; Chen, Wenlin ; Liu, Rong ; Chen, Ceshi</creator><creatorcontrib>Shi, Peiguo ; Liu, Wenjing ; Tala ; Wang, Haixia ; Li, Fubing ; Zhang, Hailin ; Wu, Yingying ; Kong, Yanjie ; Zhou, Zhongmei ; Wang, Chunyan ; Chen, Wenlin ; Liu, Rong ; Chen, Ceshi</creatorcontrib><description>Out of the breast cancer subtypes, triple-negative breast cancer (TNBC) has the poorest prognosis without effective targeted therapies. Metformin, a first-line drug for type 2 diabetes mellitus, was demonstrated to target breast cancer stem cells selectively. However, the efficiency and the mechanism of action of metformin in TNBC are unclear. In this study, we demonstrated that metformin decreased the percentage of TNBC stem cells partially through the downregulation of the expression of the stem cell transcription factor Krüppel-like factor 5 (KLF5) and its downstream target genes, such as
Nanog
and
FGF-BP1
, in TNBC cell lines. Metformin induced glycogen synthase kinase-3β (GSK3β)-mediated KLF5 protein phosphorylation and degradation through the inhibition of protein kinase A (PKA) activity in TNBC cells. Consistently, PKA activators increased the expression levels of KLF5. We observed a positive correlation between p-CREB, p-GSK3β, KLF5 and FGF-BP1 protein levels in human TNBC samples. These findings suggest that metformin suppresses TNBC stem cells partially through the PKA-GSK3β-KLF5 signaling pathway.</description><identifier>ISSN: 2056-5968</identifier><identifier>EISSN: 2056-5968</identifier><identifier>DOI: 10.1038/celldisc.2017.10</identifier><identifier>PMID: 28480051</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/1347 ; 631/80/86 ; Biomedical and Life Sciences ; Breast cancer ; Cell Biology ; Cell Culture ; Cell Cycle Analysis ; Cell Physiology ; Life Sciences ; Stem Cells</subject><ispartof>Cell discovery, 2017-04, Vol.3 (1), p.17010-17010, Article 17010</ispartof><rights>The Author(s) 2017</rights><rights>Copyright Nature Publishing Group Apr 2017</rights><rights>Copyright © 2017 The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c532t-7bf356daf9add21662038f07ab944a1ee4eb0ca1dd0221c386912ae5d2e0fe133</citedby><cites>FETCH-LOGICAL-c532t-7bf356daf9add21662038f07ab944a1ee4eb0ca1dd0221c386912ae5d2e0fe133</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396048/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396048/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,725,778,782,862,883,27907,27908,41103,42172,51559,53774,53776</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28480051$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shi, Peiguo</creatorcontrib><creatorcontrib>Liu, Wenjing</creatorcontrib><creatorcontrib>Tala</creatorcontrib><creatorcontrib>Wang, Haixia</creatorcontrib><creatorcontrib>Li, Fubing</creatorcontrib><creatorcontrib>Zhang, Hailin</creatorcontrib><creatorcontrib>Wu, Yingying</creatorcontrib><creatorcontrib>Kong, Yanjie</creatorcontrib><creatorcontrib>Zhou, Zhongmei</creatorcontrib><creatorcontrib>Wang, Chunyan</creatorcontrib><creatorcontrib>Chen, Wenlin</creatorcontrib><creatorcontrib>Liu, Rong</creatorcontrib><creatorcontrib>Chen, Ceshi</creatorcontrib><title>Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation</title><title>Cell discovery</title><addtitle>Cell Discov</addtitle><addtitle>Cell Discov</addtitle><description>Out of the breast cancer subtypes, triple-negative breast cancer (TNBC) has the poorest prognosis without effective targeted therapies. Metformin, a first-line drug for type 2 diabetes mellitus, was demonstrated to target breast cancer stem cells selectively. However, the efficiency and the mechanism of action of metformin in TNBC are unclear. In this study, we demonstrated that metformin decreased the percentage of TNBC stem cells partially through the downregulation of the expression of the stem cell transcription factor Krüppel-like factor 5 (KLF5) and its downstream target genes, such as
Nanog
and
FGF-BP1
, in TNBC cell lines. Metformin induced glycogen synthase kinase-3β (GSK3β)-mediated KLF5 protein phosphorylation and degradation through the inhibition of protein kinase A (PKA) activity in TNBC cells. Consistently, PKA activators increased the expression levels of KLF5. We observed a positive correlation between p-CREB, p-GSK3β, KLF5 and FGF-BP1 protein levels in human TNBC samples. These findings suggest that metformin suppresses TNBC stem cells partially through the PKA-GSK3β-KLF5 signaling pathway.</description><subject>631/67/1347</subject><subject>631/80/86</subject><subject>Biomedical and Life Sciences</subject><subject>Breast cancer</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell Cycle Analysis</subject><subject>Cell Physiology</subject><subject>Life Sciences</subject><subject>Stem Cells</subject><issn>2056-5968</issn><issn>2056-5968</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp1kUFv1DAQhS0EotXSOydkiQuXlLETe-0LEqpaQCziAmfLsSchVeIE26nUf4-jbasFiZOtmW_e-PkR8prBJYNavXc4jn5I7pID25fSM3LOQchKaKmen9zPyEVKtwDABFdKiZfkjKtGAQh2Tsw3zN0cpyHQtC5LxJQw0RyHZcQqYG_zcIe0jWhTps4Gh5GmjBPdtifa3tNsY495CD39ergRtIhRj320vozO4RV50dkx4cXDuSM_b65_XH2uDt8_fbn6eKicqHmu9m1XC-ltp633nEnJi8MO9rbVTWMZYoMtOMu8B86Zq5XUjFsUniN0yOp6Rz4cdZe1ndA7DDna0SxxmGy8N7MdzN-dMPwy_XxnRK0lNKoIvHsQiPPvFVM2U_nbYtIGnNdkmNKyYVzDtuvtP-jtvMZQ7BVK6VoIqZtCwZFycU4pYvf0GAZmC9A8Bmi2ALfSjrw5NfE08BhXAdgRSKUVeownm_8n-gdFEKsW</recordid><startdate>20170418</startdate><enddate>20170418</enddate><creator>Shi, Peiguo</creator><creator>Liu, Wenjing</creator><creator>Tala</creator><creator>Wang, Haixia</creator><creator>Li, Fubing</creator><creator>Zhang, Hailin</creator><creator>Wu, Yingying</creator><creator>Kong, Yanjie</creator><creator>Zhou, Zhongmei</creator><creator>Wang, Chunyan</creator><creator>Chen, Wenlin</creator><creator>Liu, Rong</creator><creator>Chen, Ceshi</creator><general>Nature Publishing Group UK</general><general>Springer Nature B.V</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170418</creationdate><title>Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation</title><author>Shi, Peiguo ; Liu, Wenjing ; Tala ; Wang, Haixia ; Li, Fubing ; Zhang, Hailin ; Wu, Yingying ; Kong, Yanjie ; Zhou, Zhongmei ; Wang, Chunyan ; Chen, Wenlin ; Liu, Rong ; Chen, Ceshi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c532t-7bf356daf9add21662038f07ab944a1ee4eb0ca1dd0221c386912ae5d2e0fe133</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>631/67/1347</topic><topic>631/80/86</topic><topic>Biomedical and Life Sciences</topic><topic>Breast cancer</topic><topic>Cell Biology</topic><topic>Cell Culture</topic><topic>Cell Cycle Analysis</topic><topic>Cell Physiology</topic><topic>Life Sciences</topic><topic>Stem Cells</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shi, Peiguo</creatorcontrib><creatorcontrib>Liu, Wenjing</creatorcontrib><creatorcontrib>Tala</creatorcontrib><creatorcontrib>Wang, Haixia</creatorcontrib><creatorcontrib>Li, Fubing</creatorcontrib><creatorcontrib>Zhang, Hailin</creatorcontrib><creatorcontrib>Wu, Yingying</creatorcontrib><creatorcontrib>Kong, Yanjie</creatorcontrib><creatorcontrib>Zhou, Zhongmei</creatorcontrib><creatorcontrib>Wang, Chunyan</creatorcontrib><creatorcontrib>Chen, Wenlin</creatorcontrib><creatorcontrib>Liu, Rong</creatorcontrib><creatorcontrib>Chen, Ceshi</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell discovery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shi, Peiguo</au><au>Liu, Wenjing</au><au>Tala</au><au>Wang, Haixia</au><au>Li, Fubing</au><au>Zhang, Hailin</au><au>Wu, Yingying</au><au>Kong, Yanjie</au><au>Zhou, Zhongmei</au><au>Wang, Chunyan</au><au>Chen, Wenlin</au><au>Liu, Rong</au><au>Chen, Ceshi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation</atitle><jtitle>Cell discovery</jtitle><stitle>Cell Discov</stitle><addtitle>Cell Discov</addtitle><date>2017-04-18</date><risdate>2017</risdate><volume>3</volume><issue>1</issue><spage>17010</spage><epage>17010</epage><pages>17010-17010</pages><artnum>17010</artnum><issn>2056-5968</issn><eissn>2056-5968</eissn><abstract>Out of the breast cancer subtypes, triple-negative breast cancer (TNBC) has the poorest prognosis without effective targeted therapies. Metformin, a first-line drug for type 2 diabetes mellitus, was demonstrated to target breast cancer stem cells selectively. However, the efficiency and the mechanism of action of metformin in TNBC are unclear. In this study, we demonstrated that metformin decreased the percentage of TNBC stem cells partially through the downregulation of the expression of the stem cell transcription factor Krüppel-like factor 5 (KLF5) and its downstream target genes, such as
Nanog
and
FGF-BP1
, in TNBC cell lines. Metformin induced glycogen synthase kinase-3β (GSK3β)-mediated KLF5 protein phosphorylation and degradation through the inhibition of protein kinase A (PKA) activity in TNBC cells. Consistently, PKA activators increased the expression levels of KLF5. We observed a positive correlation between p-CREB, p-GSK3β, KLF5 and FGF-BP1 protein levels in human TNBC samples. These findings suggest that metformin suppresses TNBC stem cells partially through the PKA-GSK3β-KLF5 signaling pathway.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28480051</pmid><doi>10.1038/celldisc.2017.10</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 631/67/1347 631/80/86 Biomedical and Life Sciences Breast cancer Cell Biology Cell Culture Cell Cycle Analysis Cell Physiology Life Sciences Stem Cells |
| title | Metformin suppresses triple-negative breast cancer stem cells by targeting KLF5 for degradation |
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