Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6/JAK2/STAT3 signaling in glioma
Purpose The iron-chelating agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has been found to inhibit cell growth and to induce apoptosis in several human cancers. However, its effects and mechanism of action in glioma are unknown. Methods Human glioma cell line LN229 and patient-d...
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| Veröffentlicht in: | Cellular oncology (Dordrecht) 2020-06, Vol.43 (3), p.461-475 |
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| creator | Zhou, Jinpeng Jiang, Yang Zhao, Junshuang Zhang, Haiying Fu, Jinlong Luo, Peng Ma, Yanju Zou, Dan Gao, Huiling Hu, Jiangfeng Zhang, Ye Jing, Zhitao |
| description | Purpose
The iron-chelating agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has been found to inhibit cell growth and to induce apoptosis in several human cancers. However, its effects and mechanism of action in glioma are unknown.
Methods
Human glioma cell line LN229 and patient-derived glioma stem cells GSC-42 were applied for both
in vitro
and
in vivo
xenograft nude mouse experiments. The anti-tumor effects of Dp44mT were assessed using MTS, EdU, TUNEL, Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation and immunohistochemical assays.
Results
We found that Dp44mT can upregulate the expression of the anti-oncogene N-myc downstream-regulated gene (NDRG)2 by directly binding to and activating the RAR-related orphan receptor (ROR)A. In addition, we found that NDRG2 overexpression suppressed inflammation via activation of interleukin (IL)-6/Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling.
Conclusions
Our data indicate that Dp44mT may serve as an effective drug for the treatment of glioma by targeting RORA and enhancing NDRG2-mediated IL-6/JAK2/STAT3 signaling. |
| doi_str_mv | 10.1007/s13402-020-00502-y |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_2401246955</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2401246955</sourcerecordid><originalsourceid>FETCH-LOGICAL-c424t-3ad1c272bb80ef1714e98c9a03549cc468c9c50cf986a34256f5dad4fa19cf083</originalsourceid><addsrcrecordid>eNp9kMtOwzAQRS0EoqjwAyyQJbaEjh9xk2XFoxQqkEpZW67jpEZtHOwEVImPx1AeO2bjGc-da89B6JjAOQEYDgJhHGgCFBKANGabHXRAKSEJ40zs_uY066GjEJ4hBhdEpGIf9RilMATOD9D7ZcP5en6GVY2tdzXWS7NSrfNnOHRN400IJuDKu7d2GTUFtnXR6XilGte0LtiAX63Cs4fZKFmbwqrWFPj-cjamyWQqBrejOzp4nI_mDAdb1Wpl6ypa4Gpl3Vodor1SrYI5-j776On6an5xk0wfxpOL0TTRnPI2Yaogmg7pYpGBKcmQcJNnOlfAUp5rzUUsdAq6zDOh4sapKNNCFbxUJNclZKyPTre-jXcvnQmtfHadj78JknIglIs8TaOKblXauxC8KWXj7Vr5jSQgP5nLLXMZmcsv5nITh06-rbtF3P935IdwFLCtIMRWXRn_9_Y_th9t4Yqr</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2401246955</pqid></control><display><type>article</type><title>Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6/JAK2/STAT3 signaling in glioma</title><source>MEDLINE</source><source>SpringerLink</source><creator>Zhou, Jinpeng ; Jiang, Yang ; Zhao, Junshuang ; Zhang, Haiying ; Fu, Jinlong ; Luo, Peng ; Ma, Yanju ; Zou, Dan ; Gao, Huiling ; Hu, Jiangfeng ; Zhang, Ye ; Jing, Zhitao</creator><creatorcontrib>Zhou, Jinpeng ; Jiang, Yang ; Zhao, Junshuang ; Zhang, Haiying ; Fu, Jinlong ; Luo, Peng ; Ma, Yanju ; Zou, Dan ; Gao, Huiling ; Hu, Jiangfeng ; Zhang, Ye ; Jing, Zhitao</creatorcontrib><description>Purpose
The iron-chelating agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has been found to inhibit cell growth and to induce apoptosis in several human cancers. However, its effects and mechanism of action in glioma are unknown.
Methods
Human glioma cell line LN229 and patient-derived glioma stem cells GSC-42 were applied for both
in vitro
and
in vivo
xenograft nude mouse experiments. The anti-tumor effects of Dp44mT were assessed using MTS, EdU, TUNEL, Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation and immunohistochemical assays.
Results
We found that Dp44mT can upregulate the expression of the anti-oncogene N-myc downstream-regulated gene (NDRG)2 by directly binding to and activating the RAR-related orphan receptor (ROR)A. In addition, we found that NDRG2 overexpression suppressed inflammation via activation of interleukin (IL)-6/Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling.
Conclusions
Our data indicate that Dp44mT may serve as an effective drug for the treatment of glioma by targeting RORA and enhancing NDRG2-mediated IL-6/JAK2/STAT3 signaling.</description><identifier>ISSN: 2211-3428</identifier><identifier>EISSN: 2211-3436</identifier><identifier>DOI: 10.1007/s13402-020-00502-y</identifier><identifier>PMID: 32207044</identifier><language>eng</language><publisher>Dordrecht: Springer Netherlands</publisher><subject>Animals ; Apoptosis ; Apoptosis - drug effects ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Carcinogenesis - drug effects ; Carcinogenesis - metabolism ; Carcinogenesis - pathology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Chelating agents ; Chromatin ; Female ; Glioma - pathology ; Glioma cells ; Humans ; Immunoprecipitation ; Interleukin 6 ; Interleukin-6 - metabolism ; Iron ; Iron Chelating Agents - pharmacology ; Janus kinase ; Janus kinase 2 ; Janus Kinase 2 - metabolism ; Mice, Inbred BALB C ; Models, Biological ; Myc protein ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Nuclear Receptor Subfamily 1, Group F, Member 1 - metabolism ; Oncology ; Original Paper ; Pathology ; Signal Transduction - drug effects ; Stat3 protein ; STAT3 Transcription Factor - metabolism ; Stem cell transplantation ; Stem cells ; Thiosemicarbazones - pharmacology ; Transcription ; Transcription, Genetic - drug effects ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - metabolism ; Western blotting ; Xenografts</subject><ispartof>Cellular oncology (Dordrecht), 2020-06, Vol.43 (3), p.461-475</ispartof><rights>International Society for Cellular Oncology 2020</rights><rights>International Society for Cellular Oncology 2020.</rights><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c424t-3ad1c272bb80ef1714e98c9a03549cc468c9c50cf986a34256f5dad4fa19cf083</citedby><cites>FETCH-LOGICAL-c424t-3ad1c272bb80ef1714e98c9a03549cc468c9c50cf986a34256f5dad4fa19cf083</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s13402-020-00502-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s13402-020-00502-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32207044$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhou, Jinpeng</creatorcontrib><creatorcontrib>Jiang, Yang</creatorcontrib><creatorcontrib>Zhao, Junshuang</creatorcontrib><creatorcontrib>Zhang, Haiying</creatorcontrib><creatorcontrib>Fu, Jinlong</creatorcontrib><creatorcontrib>Luo, Peng</creatorcontrib><creatorcontrib>Ma, Yanju</creatorcontrib><creatorcontrib>Zou, Dan</creatorcontrib><creatorcontrib>Gao, Huiling</creatorcontrib><creatorcontrib>Hu, Jiangfeng</creatorcontrib><creatorcontrib>Zhang, Ye</creatorcontrib><creatorcontrib>Jing, Zhitao</creatorcontrib><title>Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6/JAK2/STAT3 signaling in glioma</title><title>Cellular oncology (Dordrecht)</title><addtitle>Cell Oncol</addtitle><addtitle>Cell Oncol (Dordr)</addtitle><description>Purpose
The iron-chelating agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has been found to inhibit cell growth and to induce apoptosis in several human cancers. However, its effects and mechanism of action in glioma are unknown.
Methods
Human glioma cell line LN229 and patient-derived glioma stem cells GSC-42 were applied for both
in vitro
and
in vivo
xenograft nude mouse experiments. The anti-tumor effects of Dp44mT were assessed using MTS, EdU, TUNEL, Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation and immunohistochemical assays.
Results
We found that Dp44mT can upregulate the expression of the anti-oncogene N-myc downstream-regulated gene (NDRG)2 by directly binding to and activating the RAR-related orphan receptor (ROR)A. In addition, we found that NDRG2 overexpression suppressed inflammation via activation of interleukin (IL)-6/Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling.
Conclusions
Our data indicate that Dp44mT may serve as an effective drug for the treatment of glioma by targeting RORA and enhancing NDRG2-mediated IL-6/JAK2/STAT3 signaling.</description><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Carcinogenesis - drug effects</subject><subject>Carcinogenesis - metabolism</subject><subject>Carcinogenesis - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Chelating agents</subject><subject>Chromatin</subject><subject>Female</subject><subject>Glioma - pathology</subject><subject>Glioma cells</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Interleukin 6</subject><subject>Interleukin-6 - metabolism</subject><subject>Iron</subject><subject>Iron Chelating Agents - pharmacology</subject><subject>Janus kinase</subject><subject>Janus kinase 2</subject><subject>Janus Kinase 2 - metabolism</subject><subject>Mice, Inbred BALB C</subject><subject>Models, Biological</subject><subject>Myc protein</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Nuclear Receptor Subfamily 1, Group F, Member 1 - metabolism</subject><subject>Oncology</subject><subject>Original Paper</subject><subject>Pathology</subject><subject>Signal Transduction - drug effects</subject><subject>Stat3 protein</subject><subject>STAT3 Transcription Factor - metabolism</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Thiosemicarbazones - pharmacology</subject><subject>Transcription</subject><subject>Transcription, Genetic - drug effects</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - metabolism</subject><subject>Western blotting</subject><subject>Xenografts</subject><issn>2211-3428</issn><issn>2211-3436</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtOwzAQRS0EoqjwAyyQJbaEjh9xk2XFoxQqkEpZW67jpEZtHOwEVImPx1AeO2bjGc-da89B6JjAOQEYDgJhHGgCFBKANGabHXRAKSEJ40zs_uY066GjEJ4hBhdEpGIf9RilMATOD9D7ZcP5en6GVY2tdzXWS7NSrfNnOHRN400IJuDKu7d2GTUFtnXR6XilGte0LtiAX63Cs4fZKFmbwqrWFPj-cjamyWQqBrejOzp4nI_mDAdb1Wpl6ypa4Gpl3Vodor1SrYI5-j776On6an5xk0wfxpOL0TTRnPI2Yaogmg7pYpGBKcmQcJNnOlfAUp5rzUUsdAq6zDOh4sapKNNCFbxUJNclZKyPTre-jXcvnQmtfHadj78JknIglIs8TaOKblXauxC8KWXj7Vr5jSQgP5nLLXMZmcsv5nITh06-rbtF3P935IdwFLCtIMRWXRn_9_Y_th9t4Yqr</recordid><startdate>20200601</startdate><enddate>20200601</enddate><creator>Zhou, Jinpeng</creator><creator>Jiang, Yang</creator><creator>Zhao, Junshuang</creator><creator>Zhang, Haiying</creator><creator>Fu, Jinlong</creator><creator>Luo, Peng</creator><creator>Ma, Yanju</creator><creator>Zou, Dan</creator><creator>Gao, Huiling</creator><creator>Hu, Jiangfeng</creator><creator>Zhang, Ye</creator><creator>Jing, Zhitao</creator><general>Springer Netherlands</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20200601</creationdate><title>Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6/JAK2/STAT3 signaling in glioma</title><author>Zhou, Jinpeng ; Jiang, Yang ; Zhao, Junshuang ; Zhang, Haiying ; Fu, Jinlong ; Luo, Peng ; Ma, Yanju ; Zou, Dan ; Gao, Huiling ; Hu, Jiangfeng ; Zhang, Ye ; Jing, Zhitao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c424t-3ad1c272bb80ef1714e98c9a03549cc468c9c50cf986a34256f5dad4fa19cf083</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Cancer Research</topic><topic>Carcinogenesis - drug effects</topic><topic>Carcinogenesis - metabolism</topic><topic>Carcinogenesis - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Chelating agents</topic><topic>Chromatin</topic><topic>Female</topic><topic>Glioma - pathology</topic><topic>Glioma cells</topic><topic>Humans</topic><topic>Immunoprecipitation</topic><topic>Interleukin 6</topic><topic>Interleukin-6 - metabolism</topic><topic>Iron</topic><topic>Iron Chelating Agents - pharmacology</topic><topic>Janus kinase</topic><topic>Janus kinase 2</topic><topic>Janus Kinase 2 - metabolism</topic><topic>Mice, Inbred BALB C</topic><topic>Models, Biological</topic><topic>Myc protein</topic><topic>Neoplastic Stem Cells - drug effects</topic><topic>Neoplastic Stem Cells - metabolism</topic><topic>Neoplastic Stem Cells - pathology</topic><topic>Nuclear Receptor Subfamily 1, Group F, Member 1 - metabolism</topic><topic>Oncology</topic><topic>Original Paper</topic><topic>Pathology</topic><topic>Signal Transduction - drug effects</topic><topic>Stat3 protein</topic><topic>STAT3 Transcription Factor - metabolism</topic><topic>Stem cell transplantation</topic><topic>Stem cells</topic><topic>Thiosemicarbazones - pharmacology</topic><topic>Transcription</topic><topic>Transcription, Genetic - drug effects</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - metabolism</topic><topic>Western blotting</topic><topic>Xenografts</topic><toplevel>online_resources</toplevel><creatorcontrib>Zhou, Jinpeng</creatorcontrib><creatorcontrib>Jiang, Yang</creatorcontrib><creatorcontrib>Zhao, Junshuang</creatorcontrib><creatorcontrib>Zhang, Haiying</creatorcontrib><creatorcontrib>Fu, Jinlong</creatorcontrib><creatorcontrib>Luo, Peng</creatorcontrib><creatorcontrib>Ma, Yanju</creatorcontrib><creatorcontrib>Zou, Dan</creatorcontrib><creatorcontrib>Gao, Huiling</creatorcontrib><creatorcontrib>Hu, Jiangfeng</creatorcontrib><creatorcontrib>Zhang, Ye</creatorcontrib><creatorcontrib>Jing, Zhitao</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Cellular oncology (Dordrecht)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhou, Jinpeng</au><au>Jiang, Yang</au><au>Zhao, Junshuang</au><au>Zhang, Haiying</au><au>Fu, Jinlong</au><au>Luo, Peng</au><au>Ma, Yanju</au><au>Zou, Dan</au><au>Gao, Huiling</au><au>Hu, Jiangfeng</au><au>Zhang, Ye</au><au>Jing, Zhitao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6/JAK2/STAT3 signaling in glioma</atitle><jtitle>Cellular oncology (Dordrecht)</jtitle><stitle>Cell Oncol</stitle><addtitle>Cell Oncol (Dordr)</addtitle><date>2020-06-01</date><risdate>2020</risdate><volume>43</volume><issue>3</issue><spage>461</spage><epage>475</epage><pages>461-475</pages><issn>2211-3428</issn><eissn>2211-3436</eissn><abstract>Purpose
The iron-chelating agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has been found to inhibit cell growth and to induce apoptosis in several human cancers. However, its effects and mechanism of action in glioma are unknown.
Methods
Human glioma cell line LN229 and patient-derived glioma stem cells GSC-42 were applied for both
in vitro
and
in vivo
xenograft nude mouse experiments. The anti-tumor effects of Dp44mT were assessed using MTS, EdU, TUNEL, Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation and immunohistochemical assays.
Results
We found that Dp44mT can upregulate the expression of the anti-oncogene N-myc downstream-regulated gene (NDRG)2 by directly binding to and activating the RAR-related orphan receptor (ROR)A. In addition, we found that NDRG2 overexpression suppressed inflammation via activation of interleukin (IL)-6/Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling.
Conclusions
Our data indicate that Dp44mT may serve as an effective drug for the treatment of glioma by targeting RORA and enhancing NDRG2-mediated IL-6/JAK2/STAT3 signaling.</abstract><cop>Dordrecht</cop><pub>Springer Netherlands</pub><pmid>32207044</pmid><doi>10.1007/s13402-020-00502-y</doi><tpages>15</tpages></addata></record> |
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| subjects | Animals Apoptosis Apoptosis - drug effects Biomedical and Life Sciences Biomedicine Cancer Research Carcinogenesis - drug effects Carcinogenesis - metabolism Carcinogenesis - pathology Cell Line, Tumor Cell Proliferation - drug effects Chelating agents Chromatin Female Glioma - pathology Glioma cells Humans Immunoprecipitation Interleukin 6 Interleukin-6 - metabolism Iron Iron Chelating Agents - pharmacology Janus kinase Janus kinase 2 Janus Kinase 2 - metabolism Mice, Inbred BALB C Models, Biological Myc protein Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Nuclear Receptor Subfamily 1, Group F, Member 1 - metabolism Oncology Original Paper Pathology Signal Transduction - drug effects Stat3 protein STAT3 Transcription Factor - metabolism Stem cell transplantation Stem cells Thiosemicarbazones - pharmacology Transcription Transcription, Genetic - drug effects Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - metabolism Western blotting Xenografts |
| title | Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6/JAK2/STAT3 signaling in glioma |
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