DNp73 Exerts Function in Metastasis Initiation by Disconnecting the Inhibitory Role of EPLIN on IGF1R-AKT/STAT3 Signaling
Dissemination of cancer cells from primary tumors is the key event in metastasis, but specific determinants are widely unknown. Here, we show that DNp73, an inhibitor of the p53 tumor suppressor family, drives migration and invasion of nonmetastatic melanoma cells. Knockdown of endogenous DNp73 redu...
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| Veröffentlicht in: | Cancer cell 2013-10, Vol.24 (4), p.512-527 |
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| creator | Steder, Marc Alla, Vijay Meier, Claudia Spitschak, Alf Pahnke, Jens Fürst, Katharina Kowtharapu, Bhavani S. Engelmann, David Petigk, Janine Egberts, Friederike Schäd-Trcka, Susanne G. Gross, Gerd Nettelbeck, Dirk M. Niemetz, Annett Pützer, Brigitte M. |
| description | Dissemination of cancer cells from primary tumors is the key event in metastasis, but specific determinants are widely unknown. Here, we show that DNp73, an inhibitor of the p53 tumor suppressor family, drives migration and invasion of nonmetastatic melanoma cells. Knockdown of endogenous DNp73 reduces this behavior in highly metastatic cell lines. Tumor xenografts expressing DNp73 show a higher ability to invade and metastasize, while growth remains unaffected. DNp73 facilitates an EMT-like phenotype with loss of E-cadherin and Slug upregulation. We provide mechanistic insight toward regulation of LIMA1/EPLIN by p73/DNp73 and demonstrate a direct link between the DNp73-EPLIN axis and IGF1R-AKT/STAT3 activation. These findings establish initiation of the invasion-metastasis cascade via EPLIN-dependent IGF1R regulation as major activity of DNp73.
•DNp73 induces EMT, invasion, and metastasis•DNp73 interferes with p73-mediated EPLIN expression•EPLIN regulates AKT/STAT3 activities via IGF1R•DNp73 promotes EMT via the EPLIN-IGF1R-AKT/STAT3 axis |
| doi_str_mv | 10.1016/j.ccr.2013.08.023 |
| format | Article |
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•DNp73 induces EMT, invasion, and metastasis•DNp73 interferes with p73-mediated EPLIN expression•EPLIN regulates AKT/STAT3 activities via IGF1R•DNp73 promotes EMT via the EPLIN-IGF1R-AKT/STAT3 axis</description><identifier>ISSN: 1535-6108</identifier><identifier>EISSN: 1878-3686</identifier><identifier>DOI: 10.1016/j.ccr.2013.08.023</identifier><identifier>PMID: 24135282</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Cell Line, Tumor ; Cytoskeletal Proteins - metabolism ; DNA-Binding Proteins - metabolism ; DNA-Binding Proteins - physiology ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Melanoma - metabolism ; Melanoma - pathology ; Mice ; Mice, Nude ; Neoplasm Metastasis ; Neoplasm Transplantation ; Nuclear Proteins - metabolism ; Nuclear Proteins - physiology ; Proto-Oncogene Proteins c-akt - metabolism ; Receptor, IGF Type 1 - metabolism ; Signal Transduction ; Skin Neoplasms - metabolism ; Skin Neoplasms - pathology ; STAT3 Transcription Factor - metabolism ; Tumor Protein p73 ; Tumor Suppressor Protein p53 - metabolism ; Tumor Suppressor Proteins - metabolism ; Tumor Suppressor Proteins - physiology</subject><ispartof>Cancer cell, 2013-10, Vol.24 (4), p.512-527</ispartof><rights>2013 Elsevier Inc.</rights><rights>Copyright © 2013 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c462t-95ad9cf2d38f6ed9b6c92e524b60a766bac61b2cbc9c1bb930e6dd516ca9e6353</citedby><cites>FETCH-LOGICAL-c462t-95ad9cf2d38f6ed9b6c92e524b60a766bac61b2cbc9c1bb930e6dd516ca9e6353</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1535610813003693$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24135282$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Steder, Marc</creatorcontrib><creatorcontrib>Alla, Vijay</creatorcontrib><creatorcontrib>Meier, Claudia</creatorcontrib><creatorcontrib>Spitschak, Alf</creatorcontrib><creatorcontrib>Pahnke, Jens</creatorcontrib><creatorcontrib>Fürst, Katharina</creatorcontrib><creatorcontrib>Kowtharapu, Bhavani S.</creatorcontrib><creatorcontrib>Engelmann, David</creatorcontrib><creatorcontrib>Petigk, Janine</creatorcontrib><creatorcontrib>Egberts, Friederike</creatorcontrib><creatorcontrib>Schäd-Trcka, Susanne G.</creatorcontrib><creatorcontrib>Gross, Gerd</creatorcontrib><creatorcontrib>Nettelbeck, Dirk M.</creatorcontrib><creatorcontrib>Niemetz, Annett</creatorcontrib><creatorcontrib>Pützer, Brigitte M.</creatorcontrib><title>DNp73 Exerts Function in Metastasis Initiation by Disconnecting the Inhibitory Role of EPLIN on IGF1R-AKT/STAT3 Signaling</title><title>Cancer cell</title><addtitle>Cancer Cell</addtitle><description>Dissemination of cancer cells from primary tumors is the key event in metastasis, but specific determinants are widely unknown. Here, we show that DNp73, an inhibitor of the p53 tumor suppressor family, drives migration and invasion of nonmetastatic melanoma cells. Knockdown of endogenous DNp73 reduces this behavior in highly metastatic cell lines. Tumor xenografts expressing DNp73 show a higher ability to invade and metastasize, while growth remains unaffected. DNp73 facilitates an EMT-like phenotype with loss of E-cadherin and Slug upregulation. We provide mechanistic insight toward regulation of LIMA1/EPLIN by p73/DNp73 and demonstrate a direct link between the DNp73-EPLIN axis and IGF1R-AKT/STAT3 activation. These findings establish initiation of the invasion-metastasis cascade via EPLIN-dependent IGF1R regulation as major activity of DNp73.
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Alla, Vijay ; Meier, Claudia ; Spitschak, Alf ; Pahnke, Jens ; Fürst, Katharina ; Kowtharapu, Bhavani S. ; Engelmann, David ; Petigk, Janine ; Egberts, Friederike ; Schäd-Trcka, Susanne G. ; Gross, Gerd ; Nettelbeck, Dirk M. ; Niemetz, Annett ; Pützer, Brigitte M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c462t-95ad9cf2d38f6ed9b6c92e524b60a766bac61b2cbc9c1bb930e6dd516ca9e6353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Cell Line, Tumor</topic><topic>Cytoskeletal Proteins - metabolism</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>DNA-Binding Proteins - physiology</topic><topic>Female</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Melanoma - metabolism</topic><topic>Melanoma - pathology</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Neoplasm Metastasis</topic><topic>Neoplasm Transplantation</topic><topic>Nuclear Proteins - metabolism</topic><topic>Nuclear Proteins - physiology</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Receptor, IGF Type 1 - metabolism</topic><topic>Signal Transduction</topic><topic>Skin Neoplasms - metabolism</topic><topic>Skin Neoplasms - pathology</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Tumor Protein p73</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Tumor Suppressor Proteins - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Steder, Marc</creatorcontrib><creatorcontrib>Alla, Vijay</creatorcontrib><creatorcontrib>Meier, Claudia</creatorcontrib><creatorcontrib>Spitschak, Alf</creatorcontrib><creatorcontrib>Pahnke, Jens</creatorcontrib><creatorcontrib>Fürst, Katharina</creatorcontrib><creatorcontrib>Kowtharapu, Bhavani S.</creatorcontrib><creatorcontrib>Engelmann, David</creatorcontrib><creatorcontrib>Petigk, Janine</creatorcontrib><creatorcontrib>Egberts, Friederike</creatorcontrib><creatorcontrib>Schäd-Trcka, Susanne G.</creatorcontrib><creatorcontrib>Gross, Gerd</creatorcontrib><creatorcontrib>Nettelbeck, Dirk M.</creatorcontrib><creatorcontrib>Niemetz, Annett</creatorcontrib><creatorcontrib>Pützer, Brigitte M.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Steder, Marc</au><au>Alla, Vijay</au><au>Meier, Claudia</au><au>Spitschak, Alf</au><au>Pahnke, Jens</au><au>Fürst, Katharina</au><au>Kowtharapu, Bhavani S.</au><au>Engelmann, David</au><au>Petigk, Janine</au><au>Egberts, Friederike</au><au>Schäd-Trcka, Susanne G.</au><au>Gross, Gerd</au><au>Nettelbeck, Dirk M.</au><au>Niemetz, Annett</au><au>Pützer, Brigitte M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DNp73 Exerts Function in Metastasis Initiation by Disconnecting the Inhibitory Role of EPLIN on IGF1R-AKT/STAT3 Signaling</atitle><jtitle>Cancer cell</jtitle><addtitle>Cancer Cell</addtitle><date>2013-10-14</date><risdate>2013</risdate><volume>24</volume><issue>4</issue><spage>512</spage><epage>527</epage><pages>512-527</pages><issn>1535-6108</issn><eissn>1878-3686</eissn><abstract>Dissemination of cancer cells from primary tumors is the key event in metastasis, but specific determinants are widely unknown. Here, we show that DNp73, an inhibitor of the p53 tumor suppressor family, drives migration and invasion of nonmetastatic melanoma cells. Knockdown of endogenous DNp73 reduces this behavior in highly metastatic cell lines. Tumor xenografts expressing DNp73 show a higher ability to invade and metastasize, while growth remains unaffected. DNp73 facilitates an EMT-like phenotype with loss of E-cadherin and Slug upregulation. We provide mechanistic insight toward regulation of LIMA1/EPLIN by p73/DNp73 and demonstrate a direct link between the DNp73-EPLIN axis and IGF1R-AKT/STAT3 activation. These findings establish initiation of the invasion-metastasis cascade via EPLIN-dependent IGF1R regulation as major activity of DNp73.
•DNp73 induces EMT, invasion, and metastasis•DNp73 interferes with p73-mediated EPLIN expression•EPLIN regulates AKT/STAT3 activities via IGF1R•DNp73 promotes EMT via the EPLIN-IGF1R-AKT/STAT3 axis</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>24135282</pmid><doi>10.1016/j.ccr.2013.08.023</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Cell Line, Tumor Cytoskeletal Proteins - metabolism DNA-Binding Proteins - metabolism DNA-Binding Proteins - physiology Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Melanoma - metabolism Melanoma - pathology Mice Mice, Nude Neoplasm Metastasis Neoplasm Transplantation Nuclear Proteins - metabolism Nuclear Proteins - physiology Proto-Oncogene Proteins c-akt - metabolism Receptor, IGF Type 1 - metabolism Signal Transduction Skin Neoplasms - metabolism Skin Neoplasms - pathology STAT3 Transcription Factor - metabolism Tumor Protein p73 Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Proteins - metabolism Tumor Suppressor Proteins - physiology |
| title | DNp73 Exerts Function in Metastasis Initiation by Disconnecting the Inhibitory Role of EPLIN on IGF1R-AKT/STAT3 Signaling |
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