Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells
As inhibitor of apoptosis (IAP) proteins can regulate additional signaling pathways beyond apoptosis, we investigated the effect of the second mitochondrial activator of caspases (Smac) mimetic BV6, which antagonizes IAP proteins, on non-apoptotic functions in glioblastoma (GBM). Here, we identify n...
Gespeichert in:
Veröffentlicht in: | Cell death & disease 2013-03, Vol.4 (3), p.e564-e564 |
---|---|
Hauptverfasser: | , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | e564 |
---|---|
container_issue | 3 |
container_start_page | e564 |
container_title | Cell death & disease |
container_volume | 4 |
creator | Tchoghandjian, A Jennewein, C Eckhardt, I Rajalingam, K Fulda, S |
description | As inhibitor of apoptosis (IAP) proteins can regulate additional signaling pathways beyond apoptosis, we investigated the effect of the second mitochondrial activator of caspases (Smac) mimetic BV6, which antagonizes IAP proteins, on non-apoptotic functions in glioblastoma (GBM). Here, we identify non-canonical nuclear factor-
κ
B (NF-
κ
B) signaling and a tumor necrosis factor-
α
(TNF
α
)/TNF receptor 1 (TNFR1) autocrine/paracrine loop as critical mediators of BV6-stimulated migration and invasion of GBM cells. In addition to GBM cell lines, BV6 triggers cell elongation, migration and invasion in primary, patient-derived GBM cells at non-toxic concentrations, which do not affect cell viability or proliferation, and also increases infiltrative tumor growth
in vivo
underscoring the relevance of these findings. Molecular studies reveal that BV6 causes rapid degradation of cellular IAP proteins, accumulation of NIK, processing of p100 to p52, translocation of p52 into the nucleus, increased NF-
κ
B DNA binding and enhanced NF-
κ
B transcriptional activity. Electrophoretic mobility shift assay supershift shows that the NF-
κ
B DNA-binding subunits consist of p50, p52 and RelB further confirming the activation of the non-canonical NF-
κ
B pathway. BV6-stimulated NF-
κ
B activation leads to elevated mRNA levels of TNF
α
and additional NF-
κ
B target genes involved in migration (i.e., interleukin 8, monocyte chemoattractant protein 1, CXC chemokine receptor 4) and invasion (i.e., matrix metalloproteinase-9). Importantly, inhibition of NF-
κ
B by overexpression of dominant-negative I
κ
B
α
superrepressor prevents the BV6-stimulated cell elongation, migration and invasion. Similarly, specific inhibition of non-canonical NF-
κ
B signaling by RNA interference-mediated silencing of NIK suppresses the BV6-induced cell elongation, migration and invasion as well as upregulation of NF-
κ
B target genes. Intriguingly, pharmacological or genetic inhibition of the BV6-stimulated TNF
α
autocrine/paracrine loop by the TNF
α
-blocking antibody Enbrel or by knockdown of TNFR1 abrogates BV6-induced cell elongation, migration and invasion. By demonstrating that the Smac mimetic BV6 at non-toxic concentrations promotes migration and invasion of GBM cells via non-canonical NF-
κ
B signaling, our findings have important implications for the use of Smac mimetics as cancer therapeutics. |
doi_str_mv | 10.1038/cddis.2013.70 |
format | Article |
fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3615728</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1790959516</sourcerecordid><originalsourceid>FETCH-LOGICAL-c423t-a1b723944206a9a0322ef4d48b390295549e05eaa4bb0652c7070cab273d36d83</originalsourceid><addsrcrecordid>eNp1kc1u1TAQhSNERau2S7YoS1jkMv5L4g1SqSitdEUXhbU1cZzUVWIXO7lSn4L34SF4JpzmUhUkvLCtOd8ca3yy7DWBDQFWv9dta-OGAmGbCl5kRxQ4KXhdy5fP7ofZaYx3kBZjQEX5KjukTLCac3GU_bhqjZtsZzVO1rvcd7nzrtCY9lQb8i8Xxa-fH_Noe4eDdX2OMcdcBzs9yqNpLU4-LI03I-p8tKNJUhEnO84DTqZNpT6s7uja3Lodxv1T_WB9M2Cc_Jg8zTDEk-ygwyGa0_15nH27-PT1_LLYXn--Oj_bFppTNhVImooyyTmFEiUCo9R0vOV1wyRQKQSXBoRB5E0DpaC6ggo0NrRiLSvbmh1nH1bf-7lJM-j0CQEHdR_siOFBebTqb8XZW9X7nWIlERVdDN6tBrf_tF2ebdVSAwYSQPAdSezb_WPBf59NnNRo4zIuOuPnqEglQQopSJnQYkV18DEG0z15E1BL5uoxc7VkripI_JvnczzRfxJOwGYFYpJcb4K683NIWcb_OP4GKHW6KA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1790959516</pqid></control><display><type>article</type><title>Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells</title><source>MEDLINE</source><source>Nature Free</source><source>DOAJ Directory of Open Access Journals</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Springer Nature OA Free Journals</source><creator>Tchoghandjian, A ; Jennewein, C ; Eckhardt, I ; Rajalingam, K ; Fulda, S</creator><creatorcontrib>Tchoghandjian, A ; Jennewein, C ; Eckhardt, I ; Rajalingam, K ; Fulda, S</creatorcontrib><description>As inhibitor of apoptosis (IAP) proteins can regulate additional signaling pathways beyond apoptosis, we investigated the effect of the second mitochondrial activator of caspases (Smac) mimetic BV6, which antagonizes IAP proteins, on non-apoptotic functions in glioblastoma (GBM). Here, we identify non-canonical nuclear factor-
κ
B (NF-
κ
B) signaling and a tumor necrosis factor-
α
(TNF
α
)/TNF receptor 1 (TNFR1) autocrine/paracrine loop as critical mediators of BV6-stimulated migration and invasion of GBM cells. In addition to GBM cell lines, BV6 triggers cell elongation, migration and invasion in primary, patient-derived GBM cells at non-toxic concentrations, which do not affect cell viability or proliferation, and also increases infiltrative tumor growth
in vivo
underscoring the relevance of these findings. Molecular studies reveal that BV6 causes rapid degradation of cellular IAP proteins, accumulation of NIK, processing of p100 to p52, translocation of p52 into the nucleus, increased NF-
κ
B DNA binding and enhanced NF-
κ
B transcriptional activity. Electrophoretic mobility shift assay supershift shows that the NF-
κ
B DNA-binding subunits consist of p50, p52 and RelB further confirming the activation of the non-canonical NF-
κ
B pathway. BV6-stimulated NF-
κ
B activation leads to elevated mRNA levels of TNF
α
and additional NF-
κ
B target genes involved in migration (i.e., interleukin 8, monocyte chemoattractant protein 1, CXC chemokine receptor 4) and invasion (i.e., matrix metalloproteinase-9). Importantly, inhibition of NF-
κ
B by overexpression of dominant-negative I
κ
B
α
superrepressor prevents the BV6-stimulated cell elongation, migration and invasion. Similarly, specific inhibition of non-canonical NF-
κ
B signaling by RNA interference-mediated silencing of NIK suppresses the BV6-induced cell elongation, migration and invasion as well as upregulation of NF-
κ
B target genes. Intriguingly, pharmacological or genetic inhibition of the BV6-stimulated TNF
α
autocrine/paracrine loop by the TNF
α
-blocking antibody Enbrel or by knockdown of TNFR1 abrogates BV6-induced cell elongation, migration and invasion. By demonstrating that the Smac mimetic BV6 at non-toxic concentrations promotes migration and invasion of GBM cells via non-canonical NF-
κ
B signaling, our findings have important implications for the use of Smac mimetics as cancer therapeutics.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/cddis.2013.70</identifier><identifier>PMID: 23538445</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/378/1689/1690 ; 631/80/82/23 ; 631/80/84/2336 ; 631/80/86 ; Antibodies ; Apoptosis Regulatory Proteins ; Biochemistry ; Biomedical and Life Sciences ; Brain Neoplasms ; Brain Neoplasms - metabolism ; Brain Neoplasms - pathology ; Cell Biology ; Cell Culture ; Cell Line, Tumor ; Cell Movement ; Cell Movement - drug effects ; Etanercept ; Gene Expression Regulation, Neoplastic ; Gene Expression Regulation, Neoplastic - drug effects ; Glioblastoma ; Glioblastoma - metabolism ; Glioblastoma - pathology ; Humans ; Immunoglobulin G ; Immunoglobulin G - pharmacology ; Immunology ; Inhibitor of Apoptosis Proteins ; Inhibitor of Apoptosis Proteins - genetics ; Inhibitor of Apoptosis Proteins - metabolism ; Intracellular Signaling Peptides and Proteins ; Intracellular Signaling Peptides and Proteins - chemistry ; Life Sciences ; Mitochondrial Proteins ; Mitochondrial Proteins - chemistry ; Neoplasm Invasiveness ; Neoplasm Invasiveness - genetics ; Neoplasm Invasiveness - prevention & control ; NF-kappa B ; NF-kappa B - antagonists & inhibitors ; NF-kappa B - genetics ; NF-kappa B - metabolism ; Original ; original-article ; Peptidomimetics ; Peptidomimetics - pharmacology ; Protein Subunits ; Protein Subunits - antagonists & inhibitors ; Protein Subunits - genetics ; Protein Subunits - metabolism ; Receptors, Tumor Necrosis Factor ; Receptors, Tumor Necrosis Factor, Type I ; Receptors, Tumor Necrosis Factor, Type I - genetics ; Receptors, Tumor Necrosis Factor, Type I - metabolism ; RNA, Small Interfering ; RNA, Small Interfering - genetics ; Signal Transduction ; Signal Transduction - drug effects ; Tumor Necrosis Factor-alpha ; Tumor Necrosis Factor-alpha - genetics ; Tumor Necrosis Factor-alpha - metabolism</subject><ispartof>Cell death & disease, 2013-03, Vol.4 (3), p.e564-e564</ispartof><rights>The Author(s) 2013</rights><rights>Distributed under a Creative Commons Attribution 4.0 International License</rights><rights>Copyright © 2013 Macmillan Publishers Limited 2013 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c423t-a1b723944206a9a0322ef4d48b390295549e05eaa4bb0652c7070cab273d36d83</citedby><cites>FETCH-LOGICAL-c423t-a1b723944206a9a0322ef4d48b390295549e05eaa4bb0652c7070cab273d36d83</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/PMC3615728/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615728/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23538445$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://hal.science/hal-03090054$$DView record in HAL$$Hfree_for_read</backlink></links><search><creatorcontrib>Tchoghandjian, A</creatorcontrib><creatorcontrib>Jennewein, C</creatorcontrib><creatorcontrib>Eckhardt, I</creatorcontrib><creatorcontrib>Rajalingam, K</creatorcontrib><creatorcontrib>Fulda, S</creatorcontrib><title>Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>As inhibitor of apoptosis (IAP) proteins can regulate additional signaling pathways beyond apoptosis, we investigated the effect of the second mitochondrial activator of caspases (Smac) mimetic BV6, which antagonizes IAP proteins, on non-apoptotic functions in glioblastoma (GBM). Here, we identify non-canonical nuclear factor-
κ
B (NF-
κ
B) signaling and a tumor necrosis factor-
α
(TNF
α
)/TNF receptor 1 (TNFR1) autocrine/paracrine loop as critical mediators of BV6-stimulated migration and invasion of GBM cells. In addition to GBM cell lines, BV6 triggers cell elongation, migration and invasion in primary, patient-derived GBM cells at non-toxic concentrations, which do not affect cell viability or proliferation, and also increases infiltrative tumor growth
in vivo
underscoring the relevance of these findings. Molecular studies reveal that BV6 causes rapid degradation of cellular IAP proteins, accumulation of NIK, processing of p100 to p52, translocation of p52 into the nucleus, increased NF-
κ
B DNA binding and enhanced NF-
κ
B transcriptional activity. Electrophoretic mobility shift assay supershift shows that the NF-
κ
B DNA-binding subunits consist of p50, p52 and RelB further confirming the activation of the non-canonical NF-
κ
B pathway. BV6-stimulated NF-
κ
B activation leads to elevated mRNA levels of TNF
α
and additional NF-
κ
B target genes involved in migration (i.e., interleukin 8, monocyte chemoattractant protein 1, CXC chemokine receptor 4) and invasion (i.e., matrix metalloproteinase-9). Importantly, inhibition of NF-
κ
B by overexpression of dominant-negative I
κ
B
α
superrepressor prevents the BV6-stimulated cell elongation, migration and invasion. Similarly, specific inhibition of non-canonical NF-
κ
B signaling by RNA interference-mediated silencing of NIK suppresses the BV6-induced cell elongation, migration and invasion as well as upregulation of NF-
κ
B target genes. Intriguingly, pharmacological or genetic inhibition of the BV6-stimulated TNF
α
autocrine/paracrine loop by the TNF
α
-blocking antibody Enbrel or by knockdown of TNFR1 abrogates BV6-induced cell elongation, migration and invasion. By demonstrating that the Smac mimetic BV6 at non-toxic concentrations promotes migration and invasion of GBM cells via non-canonical NF-
κ
B signaling, our findings have important implications for the use of Smac mimetics as cancer therapeutics.</description><subject>631/378/1689/1690</subject><subject>631/80/82/23</subject><subject>631/80/84/2336</subject><subject>631/80/86</subject><subject>Antibodies</subject><subject>Apoptosis Regulatory Proteins</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Brain Neoplasms</subject><subject>Brain Neoplasms - metabolism</subject><subject>Brain Neoplasms - pathology</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement</subject><subject>Cell Movement - drug effects</subject><subject>Etanercept</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Glioblastoma</subject><subject>Glioblastoma - metabolism</subject><subject>Glioblastoma - pathology</subject><subject>Humans</subject><subject>Immunoglobulin G</subject><subject>Immunoglobulin G - pharmacology</subject><subject>Immunology</subject><subject>Inhibitor of Apoptosis Proteins</subject><subject>Inhibitor of Apoptosis Proteins - genetics</subject><subject>Inhibitor of Apoptosis Proteins - metabolism</subject><subject>Intracellular Signaling Peptides and Proteins</subject><subject>Intracellular Signaling Peptides and Proteins - chemistry</subject><subject>Life Sciences</subject><subject>Mitochondrial Proteins</subject><subject>Mitochondrial Proteins - chemistry</subject><subject>Neoplasm Invasiveness</subject><subject>Neoplasm Invasiveness - genetics</subject><subject>Neoplasm Invasiveness - prevention & control</subject><subject>NF-kappa B</subject><subject>NF-kappa B - antagonists & inhibitors</subject><subject>NF-kappa B - genetics</subject><subject>NF-kappa B - metabolism</subject><subject>Original</subject><subject>original-article</subject><subject>Peptidomimetics</subject><subject>Peptidomimetics - pharmacology</subject><subject>Protein Subunits</subject><subject>Protein Subunits - antagonists & inhibitors</subject><subject>Protein Subunits - genetics</subject><subject>Protein Subunits - metabolism</subject><subject>Receptors, Tumor Necrosis Factor</subject><subject>Receptors, Tumor Necrosis Factor, Type I</subject><subject>Receptors, Tumor Necrosis Factor, Type I - genetics</subject><subject>Receptors, Tumor Necrosis Factor, Type I - metabolism</subject><subject>RNA, Small Interfering</subject><subject>RNA, Small Interfering - genetics</subject><subject>Signal Transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Tumor Necrosis Factor-alpha</subject><subject>Tumor Necrosis Factor-alpha - genetics</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNp1kc1u1TAQhSNERau2S7YoS1jkMv5L4g1SqSitdEUXhbU1cZzUVWIXO7lSn4L34SF4JpzmUhUkvLCtOd8ca3yy7DWBDQFWv9dta-OGAmGbCl5kRxQ4KXhdy5fP7ofZaYx3kBZjQEX5KjukTLCac3GU_bhqjZtsZzVO1rvcd7nzrtCY9lQb8i8Xxa-fH_Noe4eDdX2OMcdcBzs9yqNpLU4-LI03I-p8tKNJUhEnO84DTqZNpT6s7uja3Lodxv1T_WB9M2Cc_Jg8zTDEk-ygwyGa0_15nH27-PT1_LLYXn--Oj_bFppTNhVImooyyTmFEiUCo9R0vOV1wyRQKQSXBoRB5E0DpaC6ggo0NrRiLSvbmh1nH1bf-7lJM-j0CQEHdR_siOFBebTqb8XZW9X7nWIlERVdDN6tBrf_tF2ebdVSAwYSQPAdSezb_WPBf59NnNRo4zIuOuPnqEglQQopSJnQYkV18DEG0z15E1BL5uoxc7VkripI_JvnczzRfxJOwGYFYpJcb4K683NIWcb_OP4GKHW6KA</recordid><startdate>20130301</startdate><enddate>20130301</enddate><creator>Tchoghandjian, A</creator><creator>Jennewein, C</creator><creator>Eckhardt, I</creator><creator>Rajalingam, K</creator><creator>Fulda, S</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>H94</scope><scope>1XC</scope><scope>5PM</scope></search><sort><creationdate>20130301</creationdate><title>Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells</title><author>Tchoghandjian, A ; Jennewein, C ; Eckhardt, I ; Rajalingam, K ; Fulda, S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c423t-a1b723944206a9a0322ef4d48b390295549e05eaa4bb0652c7070cab273d36d83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>631/378/1689/1690</topic><topic>631/80/82/23</topic><topic>631/80/84/2336</topic><topic>631/80/86</topic><topic>Antibodies</topic><topic>Apoptosis Regulatory Proteins</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Brain Neoplasms</topic><topic>Brain Neoplasms - metabolism</topic><topic>Brain Neoplasms - pathology</topic><topic>Cell Biology</topic><topic>Cell Culture</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement</topic><topic>Cell Movement - drug effects</topic><topic>Etanercept</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Glioblastoma</topic><topic>Glioblastoma - metabolism</topic><topic>Glioblastoma - pathology</topic><topic>Humans</topic><topic>Immunoglobulin G</topic><topic>Immunoglobulin G - pharmacology</topic><topic>Immunology</topic><topic>Inhibitor of Apoptosis Proteins</topic><topic>Inhibitor of Apoptosis Proteins - genetics</topic><topic>Inhibitor of Apoptosis Proteins - metabolism</topic><topic>Intracellular Signaling Peptides and Proteins</topic><topic>Intracellular Signaling Peptides and Proteins - chemistry</topic><topic>Life Sciences</topic><topic>Mitochondrial Proteins</topic><topic>Mitochondrial Proteins - chemistry</topic><topic>Neoplasm Invasiveness</topic><topic>Neoplasm Invasiveness - genetics</topic><topic>Neoplasm Invasiveness - prevention & control</topic><topic>NF-kappa B</topic><topic>NF-kappa B - antagonists & inhibitors</topic><topic>NF-kappa B - genetics</topic><topic>NF-kappa B - metabolism</topic><topic>Original</topic><topic>original-article</topic><topic>Peptidomimetics</topic><topic>Peptidomimetics - pharmacology</topic><topic>Protein Subunits</topic><topic>Protein Subunits - antagonists & inhibitors</topic><topic>Protein Subunits - genetics</topic><topic>Protein Subunits - metabolism</topic><topic>Receptors, Tumor Necrosis Factor</topic><topic>Receptors, Tumor Necrosis Factor, Type I</topic><topic>Receptors, Tumor Necrosis Factor, Type I - genetics</topic><topic>Receptors, Tumor Necrosis Factor, Type I - metabolism</topic><topic>RNA, Small Interfering</topic><topic>RNA, Small Interfering - genetics</topic><topic>Signal Transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Tumor Necrosis Factor-alpha</topic><topic>Tumor Necrosis Factor-alpha - genetics</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tchoghandjian, A</creatorcontrib><creatorcontrib>Jennewein, C</creatorcontrib><creatorcontrib>Eckhardt, I</creatorcontrib><creatorcontrib>Rajalingam, K</creatorcontrib><creatorcontrib>Fulda, S</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Hyper Article en Ligne (HAL)</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tchoghandjian, A</au><au>Jennewein, C</au><au>Eckhardt, I</au><au>Rajalingam, K</au><au>Fulda, S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2013-03-01</date><risdate>2013</risdate><volume>4</volume><issue>3</issue><spage>e564</spage><epage>e564</epage><pages>e564-e564</pages><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>As inhibitor of apoptosis (IAP) proteins can regulate additional signaling pathways beyond apoptosis, we investigated the effect of the second mitochondrial activator of caspases (Smac) mimetic BV6, which antagonizes IAP proteins, on non-apoptotic functions in glioblastoma (GBM). Here, we identify non-canonical nuclear factor-
κ
B (NF-
κ
B) signaling and a tumor necrosis factor-
α
(TNF
α
)/TNF receptor 1 (TNFR1) autocrine/paracrine loop as critical mediators of BV6-stimulated migration and invasion of GBM cells. In addition to GBM cell lines, BV6 triggers cell elongation, migration and invasion in primary, patient-derived GBM cells at non-toxic concentrations, which do not affect cell viability or proliferation, and also increases infiltrative tumor growth
in vivo
underscoring the relevance of these findings. Molecular studies reveal that BV6 causes rapid degradation of cellular IAP proteins, accumulation of NIK, processing of p100 to p52, translocation of p52 into the nucleus, increased NF-
κ
B DNA binding and enhanced NF-
κ
B transcriptional activity. Electrophoretic mobility shift assay supershift shows that the NF-
κ
B DNA-binding subunits consist of p50, p52 and RelB further confirming the activation of the non-canonical NF-
κ
B pathway. BV6-stimulated NF-
κ
B activation leads to elevated mRNA levels of TNF
α
and additional NF-
κ
B target genes involved in migration (i.e., interleukin 8, monocyte chemoattractant protein 1, CXC chemokine receptor 4) and invasion (i.e., matrix metalloproteinase-9). Importantly, inhibition of NF-
κ
B by overexpression of dominant-negative I
κ
B
α
superrepressor prevents the BV6-stimulated cell elongation, migration and invasion. Similarly, specific inhibition of non-canonical NF-
κ
B signaling by RNA interference-mediated silencing of NIK suppresses the BV6-induced cell elongation, migration and invasion as well as upregulation of NF-
κ
B target genes. Intriguingly, pharmacological or genetic inhibition of the BV6-stimulated TNF
α
autocrine/paracrine loop by the TNF
α
-blocking antibody Enbrel or by knockdown of TNFR1 abrogates BV6-induced cell elongation, migration and invasion. By demonstrating that the Smac mimetic BV6 at non-toxic concentrations promotes migration and invasion of GBM cells via non-canonical NF-
κ
B signaling, our findings have important implications for the use of Smac mimetics as cancer therapeutics.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>23538445</pmid><doi>10.1038/cddis.2013.70</doi><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 2041-4889 |
ispartof | Cell death & disease, 2013-03, Vol.4 (3), p.e564-e564 |
issn | 2041-4889 2041-4889 |
language | eng |
recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3615728 |
source | MEDLINE; Nature Free; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Springer Nature OA Free Journals |
subjects | 631/378/1689/1690 631/80/82/23 631/80/84/2336 631/80/86 Antibodies Apoptosis Regulatory Proteins Biochemistry Biomedical and Life Sciences Brain Neoplasms Brain Neoplasms - metabolism Brain Neoplasms - pathology Cell Biology Cell Culture Cell Line, Tumor Cell Movement Cell Movement - drug effects Etanercept Gene Expression Regulation, Neoplastic Gene Expression Regulation, Neoplastic - drug effects Glioblastoma Glioblastoma - metabolism Glioblastoma - pathology Humans Immunoglobulin G Immunoglobulin G - pharmacology Immunology Inhibitor of Apoptosis Proteins Inhibitor of Apoptosis Proteins - genetics Inhibitor of Apoptosis Proteins - metabolism Intracellular Signaling Peptides and Proteins Intracellular Signaling Peptides and Proteins - chemistry Life Sciences Mitochondrial Proteins Mitochondrial Proteins - chemistry Neoplasm Invasiveness Neoplasm Invasiveness - genetics Neoplasm Invasiveness - prevention & control NF-kappa B NF-kappa B - antagonists & inhibitors NF-kappa B - genetics NF-kappa B - metabolism Original original-article Peptidomimetics Peptidomimetics - pharmacology Protein Subunits Protein Subunits - antagonists & inhibitors Protein Subunits - genetics Protein Subunits - metabolism Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type I - genetics Receptors, Tumor Necrosis Factor, Type I - metabolism RNA, Small Interfering RNA, Small Interfering - genetics Signal Transduction Signal Transduction - drug effects Tumor Necrosis Factor-alpha Tumor Necrosis Factor-alpha - genetics Tumor Necrosis Factor-alpha - metabolism |
title | Identification of non-canonical NF-κB signaling as a critical mediator of Smac mimetic-stimulated migration and invasion of glioblastoma cells |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-24T17%3A07%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Identification%20of%20non-canonical%20NF-%CE%BAB%20signaling%20as%20a%20critical%20mediator%20of%20Smac%20mimetic-stimulated%20migration%20and%20invasion%20of%20glioblastoma%20cells&rft.jtitle=Cell%20death%20&%20disease&rft.au=Tchoghandjian,%20A&rft.date=2013-03-01&rft.volume=4&rft.issue=3&rft.spage=e564&rft.epage=e564&rft.pages=e564-e564&rft.issn=2041-4889&rft.eissn=2041-4889&rft_id=info:doi/10.1038/cddis.2013.70&rft_dat=%3Cproquest_pubme%3E1790959516%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1790959516&rft_id=info:pmid/23538445&rfr_iscdi=true |