Blockade of HMGB1 signaling pathway by ethyl pyruvate inhibits tumor growth in diffuse large B-cell lymphoma
High mobility group box 1 (HMGB1) protein in the tumor microenvironment actively contributes to tumor progression but its role in diffuse large B-cell lymphoma (DLBCL) is unknown. The aim of this study was to determine the mechanism by which HMGB1 promotes tumor growth in DLBCL and whether blockade...
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| Veröffentlicht in: | Cell death & disease 2019-04, Vol.10 (5), p.330-330, Article 330 |
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| description | High mobility group box 1 (HMGB1) protein in the tumor microenvironment actively contributes to tumor progression but its role in diffuse large B-cell lymphoma (DLBCL) is unknown. The aim of this study was to determine the mechanism by which HMGB1 promotes tumor growth in DLBCL and whether blockade of HMGB1 signaling pathway could inhibit tumorigenesis. We report that HMGB1 promotes proliferation of DLBCL cells by activation of AKT, extracellular signal-regulated kinases 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3) and SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase (Src). Ethyl pyruvate (EP), an anti-inflammatory agent, inhibits HMGB1 active release from DLBCL cells and significantly inhibited proliferation of DLBCL cells in vitro. Treatment with EP significantly prevented and inhibited tumor growth in vivo and prolonged DLBCL-bearing mice survival. EP significantly downregulated HMGB1 expression and phosphorylation of Src and ERK1/2 in mice lymphoma tissue. EP induced accumulation of the cell cycle inhibitor p27 but downregulated expression of cyclin-dependent kinase 2 (CDK2). Increased nuclear translocation of p27 interacted with CDK2 and cyclin A, which led to blockade of cell cycle progression at the G1 to S phase transition. In conclusion, we demonstrated for the first time that blockade of HMGB1-mediated signaling pathway by EP effectively inhibited DLBCL tumorigenesis and disease progression. |
| doi_str_mv | 10.1038/s41419-019-1563-8 |
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The aim of this study was to determine the mechanism by which HMGB1 promotes tumor growth in DLBCL and whether blockade of HMGB1 signaling pathway could inhibit tumorigenesis. We report that HMGB1 promotes proliferation of DLBCL cells by activation of AKT, extracellular signal-regulated kinases 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3) and SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase (Src). Ethyl pyruvate (EP), an anti-inflammatory agent, inhibits HMGB1 active release from DLBCL cells and significantly inhibited proliferation of DLBCL cells in vitro. Treatment with EP significantly prevented and inhibited tumor growth in vivo and prolonged DLBCL-bearing mice survival. EP significantly downregulated HMGB1 expression and phosphorylation of Src and ERK1/2 in mice lymphoma tissue. EP induced accumulation of the cell cycle inhibitor p27 but downregulated expression of cyclin-dependent kinase 2 (CDK2). Increased nuclear translocation of p27 interacted with CDK2 and cyclin A, which led to blockade of cell cycle progression at the G1 to S phase transition. In conclusion, we demonstrated for the first time that blockade of HMGB1-mediated signaling pathway by EP effectively inhibited DLBCL tumorigenesis and disease progression.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/s41419-019-1563-8</identifier><identifier>PMID: 30988279</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/106 ; 13/2 ; 13/21 ; 13/31 ; 14/35 ; 14/63 ; 631/67/1059 ; 631/67/2195 ; 631/67/327 ; 64/60 ; 692/308/153 ; 692/308/2778 ; 82/29 ; 82/80 ; AKT protein ; Animals ; Anti-Inflammatory Agents - pharmacology ; Anti-Inflammatory Agents - therapeutic use ; Antibodies ; B-cell lymphoma ; Biochemistry ; Biomedical and Life Sciences ; Cell Biology ; Cell Culture ; Cell cycle ; Cell Line, Tumor ; Cell proliferation ; Cell Proliferation - drug effects ; Cyclin A ; Cyclin-dependent kinase 2 ; Cyclin-dependent kinase inhibitor p27 ; Cyclin-Dependent Kinase Inhibitor p27 - metabolism ; Cyclin-dependent kinases ; Extracellular signal-regulated kinase ; Female ; G1 Phase Cell Cycle Checkpoints - drug effects ; High mobility group proteins ; HMGB1 protein ; HMGB1 Protein - metabolism ; Humans ; Immunology ; Inflammation ; Kinases ; Life Sciences ; Lymphocytes B ; Lymphoma ; Lymphoma, Large B-Cell, Diffuse - drug therapy ; Lymphoma, Large B-Cell, Diffuse - metabolism ; Lymphoma, Large B-Cell, Diffuse - pathology ; Mice ; Mice, Inbred BALB C ; Mitogen-Activated Protein Kinase 1 - metabolism ; Mitogen-Activated Protein Kinase 3 - metabolism ; Nuclear transport ; Phase transitions ; Phosphorylation ; Phosphorylation - drug effects ; Protein-tyrosine kinase receptors ; Proto-Oncogene Proteins c-akt - metabolism ; Pyruvates - pharmacology ; Pyruvates - therapeutic use ; Pyruvic acid ; S phase ; Signal transduction ; Signal Transduction - drug effects ; Src protein ; src-Family Kinases - metabolism ; Stat3 protein ; STAT3 Transcription Factor - metabolism ; Transcription ; Tumorigenesis</subject><ispartof>Cell death & disease, 2019-04, Vol.10 (5), p.330-330, Article 330</ispartof><rights>The Author(s) 2019</rights><rights>The Author(s) 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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The aim of this study was to determine the mechanism by which HMGB1 promotes tumor growth in DLBCL and whether blockade of HMGB1 signaling pathway could inhibit tumorigenesis. We report that HMGB1 promotes proliferation of DLBCL cells by activation of AKT, extracellular signal-regulated kinases 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3) and SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase (Src). Ethyl pyruvate (EP), an anti-inflammatory agent, inhibits HMGB1 active release from DLBCL cells and significantly inhibited proliferation of DLBCL cells in vitro. Treatment with EP significantly prevented and inhibited tumor growth in vivo and prolonged DLBCL-bearing mice survival. EP significantly downregulated HMGB1 expression and phosphorylation of Src and ERK1/2 in mice lymphoma tissue. EP induced accumulation of the cell cycle inhibitor p27 but downregulated expression of cyclin-dependent kinase 2 (CDK2). Increased nuclear translocation of p27 interacted with CDK2 and cyclin A, which led to blockade of cell cycle progression at the G1 to S phase transition. In conclusion, we demonstrated for the first time that blockade of HMGB1-mediated signaling pathway by EP effectively inhibited DLBCL tumorigenesis and disease progression.</description><subject>13/106</subject><subject>13/2</subject><subject>13/21</subject><subject>13/31</subject><subject>14/35</subject><subject>14/63</subject><subject>631/67/1059</subject><subject>631/67/2195</subject><subject>631/67/327</subject><subject>64/60</subject><subject>692/308/153</subject><subject>692/308/2778</subject><subject>82/29</subject><subject>82/80</subject><subject>AKT protein</subject><subject>Animals</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Anti-Inflammatory Agents - therapeutic use</subject><subject>Antibodies</subject><subject>B-cell lymphoma</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell cycle</subject><subject>Cell Line, Tumor</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cyclin A</subject><subject>Cyclin-dependent kinase 2</subject><subject>Cyclin-dependent kinase inhibitor p27</subject><subject>Cyclin-Dependent Kinase Inhibitor p27 - metabolism</subject><subject>Cyclin-dependent kinases</subject><subject>Extracellular signal-regulated kinase</subject><subject>Female</subject><subject>G1 Phase Cell Cycle Checkpoints - drug effects</subject><subject>High mobility group proteins</subject><subject>HMGB1 protein</subject><subject>HMGB1 Protein - metabolism</subject><subject>Humans</subject><subject>Immunology</subject><subject>Inflammation</subject><subject>Kinases</subject><subject>Life Sciences</subject><subject>Lymphocytes B</subject><subject>Lymphoma</subject><subject>Lymphoma, Large B-Cell, Diffuse - drug therapy</subject><subject>Lymphoma, Large B-Cell, Diffuse - metabolism</subject><subject>Lymphoma, Large B-Cell, Diffuse - pathology</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mitogen-Activated Protein Kinase 1 - metabolism</subject><subject>Mitogen-Activated Protein Kinase 3 - metabolism</subject><subject>Nuclear transport</subject><subject>Phase transitions</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Protein-tyrosine kinase receptors</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Pyruvates - pharmacology</subject><subject>Pyruvates - therapeutic use</subject><subject>Pyruvic acid</subject><subject>S phase</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Src protein</subject><subject>src-Family Kinases - metabolism</subject><subject>Stat3 protein</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Transcription</subject><subject>Tumorigenesis</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kV1v1yAYxYnRuGXuA3hjSLzxppPXlt6Y-F_cZjKzm3lNgNKWSUuFdku_vTSdc5pIQiA8Pw485wDwFqMzjKj4mBhmuC5QnpiXtBAvwDFBDBdMiPrls_0ROE3pDuVBKSK8fA2OKKqFIFV9DPzBB_NDNRaGFl59uzxgmFw3Ku_GDk5q7h_UCvUK7dyvHk5rXO7VbKEbe6fdnOC8DCHCLoaHuc-nsHFtuyQLvYqdhYfCWO-hX4epD4N6A161yid7-riegO8XX27Pr4rrm8uv55-vC8NpORe1aaoWNUJgwlGJDdGKsZpio7nSlcalEC1lbUk1qSjGBglNOFYlM5pgzgk9AZ923WnRg22MHeeovJyiG1RcZVBO_l0ZXS-7cC9LVnJS8Szw4VEghp-LTbMcXNpaUaMNS5KE4OxklU3M6Pt_0LuwxGzgTiHEa7oJ4p0yMaQUbfv0GYzkFqfc45Q5TrnFKTfld8-7eLrxO7wMkB1IuTR2Nv55-v-qvwBWz6q5</recordid><startdate>20190415</startdate><enddate>20190415</enddate><creator>Zhang, Tian</creator><creator>Guan, Xu-Wen</creator><creator>Gribben, John G.</creator><creator>Liu, Feng-Ting</creator><creator>Jia, Li</creator><general>Nature Publishing Group UK</general><general>Springer Nature B.V</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88I</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>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-6076-8455</orcidid></search><sort><creationdate>20190415</creationdate><title>Blockade of HMGB1 signaling pathway by ethyl pyruvate inhibits tumor growth in diffuse large B-cell lymphoma</title><author>Zhang, Tian ; Guan, Xu-Wen ; Gribben, John G. ; Liu, Feng-Ting ; Jia, Li</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c536t-9cd7f0d88125061c2ba44931cb5ab7b1688f34f63b27311c08b251a64cb215523</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>13/106</topic><topic>13/2</topic><topic>13/21</topic><topic>13/31</topic><topic>14/35</topic><topic>14/63</topic><topic>631/67/1059</topic><topic>631/67/2195</topic><topic>631/67/327</topic><topic>64/60</topic><topic>692/308/153</topic><topic>692/308/2778</topic><topic>82/29</topic><topic>82/80</topic><topic>AKT protein</topic><topic>Animals</topic><topic>Anti-Inflammatory Agents - pharmacology</topic><topic>Anti-Inflammatory Agents - therapeutic use</topic><topic>Antibodies</topic><topic>B-cell lymphoma</topic><topic>Biochemistry</topic><topic>Biomedical and Life Sciences</topic><topic>Cell Biology</topic><topic>Cell Culture</topic><topic>Cell cycle</topic><topic>Cell Line, Tumor</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Cyclin A</topic><topic>Cyclin-dependent kinase 2</topic><topic>Cyclin-dependent kinase inhibitor p27</topic><topic>Cyclin-Dependent Kinase Inhibitor p27 - metabolism</topic><topic>Cyclin-dependent kinases</topic><topic>Extracellular signal-regulated kinase</topic><topic>Female</topic><topic>G1 Phase Cell Cycle Checkpoints - drug effects</topic><topic>High mobility group proteins</topic><topic>HMGB1 protein</topic><topic>HMGB1 Protein - metabolism</topic><topic>Humans</topic><topic>Immunology</topic><topic>Inflammation</topic><topic>Kinases</topic><topic>Life Sciences</topic><topic>Lymphocytes B</topic><topic>Lymphoma</topic><topic>Lymphoma, Large B-Cell, Diffuse - drug therapy</topic><topic>Lymphoma, Large B-Cell, Diffuse - metabolism</topic><topic>Lymphoma, Large B-Cell, Diffuse - pathology</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mitogen-Activated Protein Kinase 1 - metabolism</topic><topic>Mitogen-Activated Protein Kinase 3 - metabolism</topic><topic>Nuclear transport</topic><topic>Phase transitions</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Protein-tyrosine kinase receptors</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Pyruvates - pharmacology</topic><topic>Pyruvates - therapeutic use</topic><topic>Pyruvic acid</topic><topic>S phase</topic><topic>Signal transduction</topic><topic>Signal Transduction - drug effects</topic><topic>Src protein</topic><topic>src-Family Kinases - metabolism</topic><topic>Stat3 protein</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Transcription</topic><topic>Tumorigenesis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Tian</creatorcontrib><creatorcontrib>Guan, Xu-Wen</creatorcontrib><creatorcontrib>Gribben, John G.</creatorcontrib><creatorcontrib>Liu, Feng-Ting</creatorcontrib><creatorcontrib>Jia, Li</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>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</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>Science Database</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>ProQuest Central Basic</collection><collection>MEDLINE - Academic</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>Zhang, Tian</au><au>Guan, Xu-Wen</au><au>Gribben, John G.</au><au>Liu, Feng-Ting</au><au>Jia, Li</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Blockade of HMGB1 signaling pathway by ethyl pyruvate inhibits tumor growth in diffuse large B-cell lymphoma</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2019-04-15</date><risdate>2019</risdate><volume>10</volume><issue>5</issue><spage>330</spage><epage>330</epage><pages>330-330</pages><artnum>330</artnum><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>High mobility group box 1 (HMGB1) protein in the tumor microenvironment actively contributes to tumor progression but its role in diffuse large B-cell lymphoma (DLBCL) is unknown. The aim of this study was to determine the mechanism by which HMGB1 promotes tumor growth in DLBCL and whether blockade of HMGB1 signaling pathway could inhibit tumorigenesis. We report that HMGB1 promotes proliferation of DLBCL cells by activation of AKT, extracellular signal-regulated kinases 1/2 (ERK1/2), signal transducer and activator of transcription 3 (STAT3) and SRC Proto-Oncogene, Non-Receptor Tyrosine Kinase (Src). Ethyl pyruvate (EP), an anti-inflammatory agent, inhibits HMGB1 active release from DLBCL cells and significantly inhibited proliferation of DLBCL cells in vitro. Treatment with EP significantly prevented and inhibited tumor growth in vivo and prolonged DLBCL-bearing mice survival. EP significantly downregulated HMGB1 expression and phosphorylation of Src and ERK1/2 in mice lymphoma tissue. EP induced accumulation of the cell cycle inhibitor p27 but downregulated expression of cyclin-dependent kinase 2 (CDK2). Increased nuclear translocation of p27 interacted with CDK2 and cyclin A, which led to blockade of cell cycle progression at the G1 to S phase transition. In conclusion, we demonstrated for the first time that blockade of HMGB1-mediated signaling pathway by EP effectively inhibited DLBCL tumorigenesis and disease progression.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>30988279</pmid><doi>10.1038/s41419-019-1563-8</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-6076-8455</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/106 13/2 13/21 13/31 14/35 14/63 631/67/1059 631/67/2195 631/67/327 64/60 692/308/153 692/308/2778 82/29 82/80 AKT protein Animals Anti-Inflammatory Agents - pharmacology Anti-Inflammatory Agents - therapeutic use Antibodies B-cell lymphoma Biochemistry Biomedical and Life Sciences Cell Biology Cell Culture Cell cycle Cell Line, Tumor Cell proliferation Cell Proliferation - drug effects Cyclin A Cyclin-dependent kinase 2 Cyclin-dependent kinase inhibitor p27 Cyclin-Dependent Kinase Inhibitor p27 - metabolism Cyclin-dependent kinases Extracellular signal-regulated kinase Female G1 Phase Cell Cycle Checkpoints - drug effects High mobility group proteins HMGB1 protein HMGB1 Protein - metabolism Humans Immunology Inflammation Kinases Life Sciences Lymphocytes B Lymphoma Lymphoma, Large B-Cell, Diffuse - drug therapy Lymphoma, Large B-Cell, Diffuse - metabolism Lymphoma, Large B-Cell, Diffuse - pathology Mice Mice, Inbred BALB C Mitogen-Activated Protein Kinase 1 - metabolism Mitogen-Activated Protein Kinase 3 - metabolism Nuclear transport Phase transitions Phosphorylation Phosphorylation - drug effects Protein-tyrosine kinase receptors Proto-Oncogene Proteins c-akt - metabolism Pyruvates - pharmacology Pyruvates - therapeutic use Pyruvic acid S phase Signal transduction Signal Transduction - drug effects Src protein src-Family Kinases - metabolism Stat3 protein STAT3 Transcription Factor - metabolism Transcription Tumorigenesis |
| title | Blockade of HMGB1 signaling pathway by ethyl pyruvate inhibits tumor growth in diffuse large B-cell lymphoma |
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