Down-regulation of Cbl-b by bufalin results in up-regulation of DR4/DR5 and sensitization of TRAIL-induced apoptosis in breast cancer cells
Purpose TNF-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic agent that preferentially induces apoptosis in cancer cells. However, breast cancer cells are generally resistant to TRAIL. Bufalin is a major active ingredient of the traditional Chinese medicine ChanSu. The pre...
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| Veröffentlicht in: | Journal of cancer research and clinical oncology 2012-08, Vol.138 (8), p.1279-1289 |
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| container_title | Journal of cancer research and clinical oncology |
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| creator | Yan, Shunchao Qu, Xiujuan Xu, Chong’an Zhu, Zhitu Zhang, Lingyun Xu, Ling Song, Na Teng, Yuee Liu, Yunpeng |
| description | Purpose
TNF-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic agent that preferentially induces apoptosis in cancer cells. However, breast cancer cells are generally resistant to TRAIL. Bufalin is a major active ingredient of the traditional Chinese medicine ChanSu. The present study aimed to assess the synergistic effect of bufalin and TRAIL and elucidate the underlying mechanisms in breast cancer cells.
Methods
Cell proliferation and apoptosis were measured by MTT assay and flow cytometry, respectively. The expression of proteins was assayed by flow cytometry and/or Western blotting. Transfection studies were used to determine the involvement of DR4, DR5 and Cbl-b in the synergistic effect of bufalin and TRAIL.
Results
MCF-7 and MDA-MB-231 cells were resistant to TRAIL. Both cell lines were dramatically sensitized to TRAIL-induced apoptosis by bufalin. Further experiments indicated that bufalin up-regulated DR4 and DR5, activated ERK, JNK and p38 MAPK and down-regulated Cbl-b. Blocking the up-regulation of DR4 and DR5 by siRNA rendered cells less sensitive to apoptosis induced by the combination of bufalin and TRAIL. Inhibition of the activation of ERK, JNK and p38 MAPK by specific inhibitors attenuated DR4 and DR5 up-regulation. Moreover, down-regulation of Cbl-b by shRNA led to stronger activation of ERK, JNK and p38 MAPK, more up-regulation of DR4 and DR5, and a stronger synergistic effect of bufalin and TRAIL.
Conclusions
Bufalin enhanced TRAIL-induced apoptosis by up-regulating the expression of DR4 and DR5. Bufalin-induced down-regulation of Cbl-b contributed to the up-regulation of DR4 and DR5, which might be partially mediated by the activation of ERK, JNK and p38 MAPK. |
| doi_str_mv | 10.1007/s00432-012-1204-4 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_journals_1026666045</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2713186541</sourcerecordid><originalsourceid>FETCH-LOGICAL-c402t-984a52b7f20b99be486386c432597fa59d6dec0b25f2293f096c2c47bc3dbf0e3</originalsourceid><addsrcrecordid>eNp1kN9q2zAUxsVoWbN2D7CbIii71HokS3J8WZJtLQQKIb02kiwVF1f2dGxG-wp76SlLmpZBdaM_53e-T-cj5AuHbxygvEQAWQgGXDAuQDL5gcz49oUXhToiM-AlZ0pwfUI-IT5AvqtSfCQnQkhZgoQZ-bPsf0eW_P3UmbHtI-0DXdiOWWqfqJ2C6dpIk8epG5Hm4zT8By_X8nK5VtTEhqKP2I7t86G4WV_drFgbm8n5hpqhH8Ye239CNnmDI3UmOp-o812HZ-Q4-6H_vN9Pyd2P75vFNVvd_rxZXK2YkyBGVs2lUcKWQYCtKuvlXBdz7fLcqiqDUVWjG-_AChWEqIoAlXbCydK6orEBfHFKLna6Q-p_TR7H-qGfUsyWNQeh8wKpMsV3lEs9YvKhHlL7aNJThupt_PUu_jrHX2_jr2XuOd8rT_bRN4eOl7wz8HUPGHSmCymP3-Irp7nmoHXmxI7DXIr3Pr394nvufwGpGpyF</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1026666045</pqid></control><display><type>article</type><title>Down-regulation of Cbl-b by bufalin results in up-regulation of DR4/DR5 and sensitization of TRAIL-induced apoptosis in breast cancer cells</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><creator>Yan, Shunchao ; Qu, Xiujuan ; Xu, Chong’an ; Zhu, Zhitu ; Zhang, Lingyun ; Xu, Ling ; Song, Na ; Teng, Yuee ; Liu, Yunpeng</creator><creatorcontrib>Yan, Shunchao ; Qu, Xiujuan ; Xu, Chong’an ; Zhu, Zhitu ; Zhang, Lingyun ; Xu, Ling ; Song, Na ; Teng, Yuee ; Liu, Yunpeng</creatorcontrib><description>Purpose
TNF-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic agent that preferentially induces apoptosis in cancer cells. However, breast cancer cells are generally resistant to TRAIL. Bufalin is a major active ingredient of the traditional Chinese medicine ChanSu. The present study aimed to assess the synergistic effect of bufalin and TRAIL and elucidate the underlying mechanisms in breast cancer cells.
Methods
Cell proliferation and apoptosis were measured by MTT assay and flow cytometry, respectively. The expression of proteins was assayed by flow cytometry and/or Western blotting. Transfection studies were used to determine the involvement of DR4, DR5 and Cbl-b in the synergistic effect of bufalin and TRAIL.
Results
MCF-7 and MDA-MB-231 cells were resistant to TRAIL. Both cell lines were dramatically sensitized to TRAIL-induced apoptosis by bufalin. Further experiments indicated that bufalin up-regulated DR4 and DR5, activated ERK, JNK and p38 MAPK and down-regulated Cbl-b. Blocking the up-regulation of DR4 and DR5 by siRNA rendered cells less sensitive to apoptosis induced by the combination of bufalin and TRAIL. Inhibition of the activation of ERK, JNK and p38 MAPK by specific inhibitors attenuated DR4 and DR5 up-regulation. Moreover, down-regulation of Cbl-b by shRNA led to stronger activation of ERK, JNK and p38 MAPK, more up-regulation of DR4 and DR5, and a stronger synergistic effect of bufalin and TRAIL.
Conclusions
Bufalin enhanced TRAIL-induced apoptosis by up-regulating the expression of DR4 and DR5. Bufalin-induced down-regulation of Cbl-b contributed to the up-regulation of DR4 and DR5, which might be partially mediated by the activation of ERK, JNK and p38 MAPK.</description><identifier>ISSN: 0171-5216</identifier><identifier>EISSN: 1432-1335</identifier><identifier>DOI: 10.1007/s00432-012-1204-4</identifier><identifier>PMID: 22447040</identifier><identifier>CODEN: JCROD7</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Animals ; Antineoplastic agents ; Apoptosis - drug effects ; Biological and medical sciences ; Blotting, Western ; Breast cancer ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Bufanolides - pharmacology ; Cancer Research ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Cellular biology ; Down-Regulation - drug effects ; Drug resistance ; Drug Synergism ; Drug therapy ; Enzyme Inhibitors - pharmacology ; Female ; Gynecology. Andrology. Obstetrics ; Hematology ; Humans ; Internal Medicine ; Mammary gland diseases ; Mammary Neoplasms, Experimental - drug therapy ; Mammary Neoplasms, Experimental - genetics ; Mammary Neoplasms, Experimental - metabolism ; Medical sciences ; Medicine ; Medicine & Public Health ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Mitogen-Activated Protein Kinases - antagonists & inhibitors ; Mitogen-Activated Protein Kinases - metabolism ; Oncology ; Original Paper ; Pharmacology. Drug treatments ; Proto-Oncogene Proteins c-cbl - genetics ; Proto-Oncogene Proteins c-cbl - metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics ; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism ; RNA Interference ; TNF-Related Apoptosis-Inducing Ligand - pharmacology ; Tumors ; Up-Regulation - drug effects ; Xenograft Model Antitumor Assays</subject><ispartof>Journal of cancer research and clinical oncology, 2012-08, Vol.138 (8), p.1279-1289</ispartof><rights>Springer-Verlag 2012</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c402t-984a52b7f20b99be486386c432597fa59d6dec0b25f2293f096c2c47bc3dbf0e3</citedby><cites>FETCH-LOGICAL-c402t-984a52b7f20b99be486386c432597fa59d6dec0b25f2293f096c2c47bc3dbf0e3</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/s00432-012-1204-4$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00432-012-1204-4$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=26161066$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22447040$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yan, Shunchao</creatorcontrib><creatorcontrib>Qu, Xiujuan</creatorcontrib><creatorcontrib>Xu, Chong’an</creatorcontrib><creatorcontrib>Zhu, Zhitu</creatorcontrib><creatorcontrib>Zhang, Lingyun</creatorcontrib><creatorcontrib>Xu, Ling</creatorcontrib><creatorcontrib>Song, Na</creatorcontrib><creatorcontrib>Teng, Yuee</creatorcontrib><creatorcontrib>Liu, Yunpeng</creatorcontrib><title>Down-regulation of Cbl-b by bufalin results in up-regulation of DR4/DR5 and sensitization of TRAIL-induced apoptosis in breast cancer cells</title><title>Journal of cancer research and clinical oncology</title><addtitle>J Cancer Res Clin Oncol</addtitle><addtitle>J Cancer Res Clin Oncol</addtitle><description>Purpose
TNF-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic agent that preferentially induces apoptosis in cancer cells. However, breast cancer cells are generally resistant to TRAIL. Bufalin is a major active ingredient of the traditional Chinese medicine ChanSu. The present study aimed to assess the synergistic effect of bufalin and TRAIL and elucidate the underlying mechanisms in breast cancer cells.
Methods
Cell proliferation and apoptosis were measured by MTT assay and flow cytometry, respectively. The expression of proteins was assayed by flow cytometry and/or Western blotting. Transfection studies were used to determine the involvement of DR4, DR5 and Cbl-b in the synergistic effect of bufalin and TRAIL.
Results
MCF-7 and MDA-MB-231 cells were resistant to TRAIL. Both cell lines were dramatically sensitized to TRAIL-induced apoptosis by bufalin. Further experiments indicated that bufalin up-regulated DR4 and DR5, activated ERK, JNK and p38 MAPK and down-regulated Cbl-b. Blocking the up-regulation of DR4 and DR5 by siRNA rendered cells less sensitive to apoptosis induced by the combination of bufalin and TRAIL. Inhibition of the activation of ERK, JNK and p38 MAPK by specific inhibitors attenuated DR4 and DR5 up-regulation. Moreover, down-regulation of Cbl-b by shRNA led to stronger activation of ERK, JNK and p38 MAPK, more up-regulation of DR4 and DR5, and a stronger synergistic effect of bufalin and TRAIL.
Conclusions
Bufalin enhanced TRAIL-induced apoptosis by up-regulating the expression of DR4 and DR5. Bufalin-induced down-regulation of Cbl-b contributed to the up-regulation of DR4 and DR5, which might be partially mediated by the activation of ERK, JNK and p38 MAPK.</description><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Apoptosis - drug effects</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Bufanolides - pharmacology</subject><subject>Cancer Research</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Cellular biology</subject><subject>Down-Regulation - drug effects</subject><subject>Drug resistance</subject><subject>Drug Synergism</subject><subject>Drug therapy</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Female</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Hematology</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Mammary gland diseases</subject><subject>Mammary Neoplasms, Experimental - drug therapy</subject><subject>Mammary Neoplasms, Experimental - genetics</subject><subject>Mammary Neoplasms, Experimental - metabolism</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Mitogen-Activated Protein Kinases - antagonists & inhibitors</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Oncology</subject><subject>Original Paper</subject><subject>Pharmacology. Drug treatments</subject><subject>Proto-Oncogene Proteins c-cbl - genetics</subject><subject>Proto-Oncogene Proteins c-cbl - metabolism</subject><subject>Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics</subject><subject>Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism</subject><subject>RNA Interference</subject><subject>TNF-Related Apoptosis-Inducing Ligand - pharmacology</subject><subject>Tumors</subject><subject>Up-Regulation - drug effects</subject><subject>Xenograft Model Antitumor Assays</subject><issn>0171-5216</issn><issn>1432-1335</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kN9q2zAUxsVoWbN2D7CbIii71HokS3J8WZJtLQQKIb02kiwVF1f2dGxG-wp76SlLmpZBdaM_53e-T-cj5AuHbxygvEQAWQgGXDAuQDL5gcz49oUXhToiM-AlZ0pwfUI-IT5AvqtSfCQnQkhZgoQZ-bPsf0eW_P3UmbHtI-0DXdiOWWqfqJ2C6dpIk8epG5Hm4zT8By_X8nK5VtTEhqKP2I7t86G4WV_drFgbm8n5hpqhH8Ye239CNnmDI3UmOp-o812HZ-Q4-6H_vN9Pyd2P75vFNVvd_rxZXK2YkyBGVs2lUcKWQYCtKuvlXBdz7fLcqiqDUVWjG-_AChWEqIoAlXbCydK6orEBfHFKLna6Q-p_TR7H-qGfUsyWNQeh8wKpMsV3lEs9YvKhHlL7aNJThupt_PUu_jrHX2_jr2XuOd8rT_bRN4eOl7wz8HUPGHSmCymP3-Irp7nmoHXmxI7DXIr3Pr394nvufwGpGpyF</recordid><startdate>20120801</startdate><enddate>20120801</enddate><creator>Yan, Shunchao</creator><creator>Qu, Xiujuan</creator><creator>Xu, Chong’an</creator><creator>Zhu, Zhitu</creator><creator>Zhang, Lingyun</creator><creator>Xu, Ling</creator><creator>Song, Na</creator><creator>Teng, Yuee</creator><creator>Liu, Yunpeng</creator><general>Springer-Verlag</general><general>Springer</general><general>Springer Nature B.V</general><scope>IQODW</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>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>K9.</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope></search><sort><creationdate>20120801</creationdate><title>Down-regulation of Cbl-b by bufalin results in up-regulation of DR4/DR5 and sensitization of TRAIL-induced apoptosis in breast cancer cells</title><author>Yan, Shunchao ; Qu, Xiujuan ; Xu, Chong’an ; Zhu, Zhitu ; Zhang, Lingyun ; Xu, Ling ; Song, Na ; Teng, Yuee ; Liu, Yunpeng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c402t-984a52b7f20b99be486386c432597fa59d6dec0b25f2293f096c2c47bc3dbf0e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Adaptor Proteins, Signal Transducing - genetics</topic><topic>Adaptor Proteins, Signal Transducing - metabolism</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Apoptosis - drug effects</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Bufanolides - pharmacology</topic><topic>Cancer Research</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Cellular biology</topic><topic>Down-Regulation - drug effects</topic><topic>Drug resistance</topic><topic>Drug Synergism</topic><topic>Drug therapy</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Female</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Hematology</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Mammary gland diseases</topic><topic>Mammary Neoplasms, Experimental - drug therapy</topic><topic>Mammary Neoplasms, Experimental - genetics</topic><topic>Mammary Neoplasms, Experimental - metabolism</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Mitogen-Activated Protein Kinases - antagonists & inhibitors</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Oncology</topic><topic>Original Paper</topic><topic>Pharmacology. Drug treatments</topic><topic>Proto-Oncogene Proteins c-cbl - genetics</topic><topic>Proto-Oncogene Proteins c-cbl - metabolism</topic><topic>Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics</topic><topic>Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism</topic><topic>RNA Interference</topic><topic>TNF-Related Apoptosis-Inducing Ligand - pharmacology</topic><topic>Tumors</topic><topic>Up-Regulation - drug effects</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yan, Shunchao</creatorcontrib><creatorcontrib>Qu, Xiujuan</creatorcontrib><creatorcontrib>Xu, Chong’an</creatorcontrib><creatorcontrib>Zhu, Zhitu</creatorcontrib><creatorcontrib>Zhang, Lingyun</creatorcontrib><creatorcontrib>Xu, Ling</creatorcontrib><creatorcontrib>Song, Na</creatorcontrib><creatorcontrib>Teng, Yuee</creatorcontrib><creatorcontrib>Liu, Yunpeng</creatorcontrib><collection>Pascal-Francis</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>Oncogenes and Growth Factors Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</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>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Research Library (Corporate)</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><jtitle>Journal of cancer research and clinical oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yan, Shunchao</au><au>Qu, Xiujuan</au><au>Xu, Chong’an</au><au>Zhu, Zhitu</au><au>Zhang, Lingyun</au><au>Xu, Ling</au><au>Song, Na</au><au>Teng, Yuee</au><au>Liu, Yunpeng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Down-regulation of Cbl-b by bufalin results in up-regulation of DR4/DR5 and sensitization of TRAIL-induced apoptosis in breast cancer cells</atitle><jtitle>Journal of cancer research and clinical oncology</jtitle><stitle>J Cancer Res Clin Oncol</stitle><addtitle>J Cancer Res Clin Oncol</addtitle><date>2012-08-01</date><risdate>2012</risdate><volume>138</volume><issue>8</issue><spage>1279</spage><epage>1289</epage><pages>1279-1289</pages><issn>0171-5216</issn><eissn>1432-1335</eissn><coden>JCROD7</coden><abstract>Purpose
TNF-related apoptosis-inducing ligand (TRAIL) is a potential cancer therapeutic agent that preferentially induces apoptosis in cancer cells. However, breast cancer cells are generally resistant to TRAIL. Bufalin is a major active ingredient of the traditional Chinese medicine ChanSu. The present study aimed to assess the synergistic effect of bufalin and TRAIL and elucidate the underlying mechanisms in breast cancer cells.
Methods
Cell proliferation and apoptosis were measured by MTT assay and flow cytometry, respectively. The expression of proteins was assayed by flow cytometry and/or Western blotting. Transfection studies were used to determine the involvement of DR4, DR5 and Cbl-b in the synergistic effect of bufalin and TRAIL.
Results
MCF-7 and MDA-MB-231 cells were resistant to TRAIL. Both cell lines were dramatically sensitized to TRAIL-induced apoptosis by bufalin. Further experiments indicated that bufalin up-regulated DR4 and DR5, activated ERK, JNK and p38 MAPK and down-regulated Cbl-b. Blocking the up-regulation of DR4 and DR5 by siRNA rendered cells less sensitive to apoptosis induced by the combination of bufalin and TRAIL. Inhibition of the activation of ERK, JNK and p38 MAPK by specific inhibitors attenuated DR4 and DR5 up-regulation. Moreover, down-regulation of Cbl-b by shRNA led to stronger activation of ERK, JNK and p38 MAPK, more up-regulation of DR4 and DR5, and a stronger synergistic effect of bufalin and TRAIL.
Conclusions
Bufalin enhanced TRAIL-induced apoptosis by up-regulating the expression of DR4 and DR5. Bufalin-induced down-regulation of Cbl-b contributed to the up-regulation of DR4 and DR5, which might be partially mediated by the activation of ERK, JNK and p38 MAPK.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>22447040</pmid><doi>10.1007/s00432-012-1204-4</doi><tpages>11</tpages></addata></record> |
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| subjects | Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Animals Antineoplastic agents Apoptosis - drug effects Biological and medical sciences Blotting, Western Breast cancer Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Bufanolides - pharmacology Cancer Research Cell Line, Tumor Cell Proliferation - drug effects Cellular biology Down-Regulation - drug effects Drug resistance Drug Synergism Drug therapy Enzyme Inhibitors - pharmacology Female Gynecology. Andrology. Obstetrics Hematology Humans Internal Medicine Mammary gland diseases Mammary Neoplasms, Experimental - drug therapy Mammary Neoplasms, Experimental - genetics Mammary Neoplasms, Experimental - metabolism Medical sciences Medicine Medicine & Public Health Mice Mice, Inbred BALB C Mice, Nude Mitogen-Activated Protein Kinases - antagonists & inhibitors Mitogen-Activated Protein Kinases - metabolism Oncology Original Paper Pharmacology. Drug treatments Proto-Oncogene Proteins c-cbl - genetics Proto-Oncogene Proteins c-cbl - metabolism Receptors, TNF-Related Apoptosis-Inducing Ligand - genetics Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism RNA Interference TNF-Related Apoptosis-Inducing Ligand - pharmacology Tumors Up-Regulation - drug effects Xenograft Model Antitumor Assays |
| title | Down-regulation of Cbl-b by bufalin results in up-regulation of DR4/DR5 and sensitization of TRAIL-induced apoptosis in breast cancer cells |
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