Disrupting CCT-β : β-tubulin selectively kills CCT-β overexpressed cancer cells through MAPKs activation
We have previously demonstrated the ability of I-Trp to disrupt the protein–protein interaction of β -tubulin with chaperonin-containing TCP-1 β (CCT- β ). This caused more severe apoptosis in multidrug-resistant MES-SA/Dx5, compared to MES-SA, due to its higher CCT- β overexpression. In this study,...
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| Veröffentlicht in: | Cell death & disease 2017-09, Vol.8 (9), p.e3052-e3052 |
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| creator | Liu, Yan-Jin Kumar, Vathan Lin, Yuan-Feng Liang, Po-Huang |
| description | We have previously demonstrated the ability of I-Trp to disrupt the protein–protein interaction of
β
-tubulin with chaperonin-containing TCP-1
β
(CCT-
β
). This caused more severe apoptosis in multidrug-resistant MES-SA/Dx5, compared to MES-SA, due to its higher CCT-
β
overexpression. In this study, we screened a panel of cancer cell lines, finding CCT-
β
overexpression in the triple-negative breast cancer cell line MDA-MB-231, colorectal cancer cell lines Colo205 and HCT116, and a gastric cancer cell line MKN-45. Thus, I-Trp killed these cancers with sub- to low-
μ
M EC
50
, whereas it was non-toxic to MCF-10A. We then synthesized analogs of I-Trp and evaluated their cytotoxicity. Furthermore, apoptotic mechanism investigations revealed the activation of both protein ubiquitination/degradation and ER-associated protein degradation pathways. These pathways proceeded through activation of MAPKs at the onset of CCT-
β
:
β
-tubulin complex disruption. We thus establish an effective strategy to treat CCT-
β
overexpressed cancers by disrupting the CCT-
β
:
β
-tubulin complex. |
| doi_str_mv | 10.1038/cddis.2017.425 |
| format | Article |
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β
-tubulin with chaperonin-containing TCP-1
β
(CCT-
β
). This caused more severe apoptosis in multidrug-resistant MES-SA/Dx5, compared to MES-SA, due to its higher CCT-
β
overexpression. In this study, we screened a panel of cancer cell lines, finding CCT-
β
overexpression in the triple-negative breast cancer cell line MDA-MB-231, colorectal cancer cell lines Colo205 and HCT116, and a gastric cancer cell line MKN-45. Thus, I-Trp killed these cancers with sub- to low-
μ
M EC
50
, whereas it was non-toxic to MCF-10A. We then synthesized analogs of I-Trp and evaluated their cytotoxicity. Furthermore, apoptotic mechanism investigations revealed the activation of both protein ubiquitination/degradation and ER-associated protein degradation pathways. These pathways proceeded through activation of MAPKs at the onset of CCT-
β
:
β
-tubulin complex disruption. We thus establish an effective strategy to treat CCT-
β
overexpressed cancers by disrupting the CCT-
β
:
β
-tubulin complex.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/cddis.2017.425</identifier><identifier>PMID: 28906489</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/2 ; 13/31 ; 13/95 ; 14/63 ; 38/89 ; 42/109 ; 631/45/612/1228 ; 631/67/1059 ; 631/80/82/23 ; 631/80/86 ; Antibodies ; Apoptosis - drug effects ; Biochemistry ; Calcium - metabolism ; Caspases - metabolism ; Cell Biology ; Cell Culture ; Cell Line, Tumor ; Chaperonin Containing TCP-1 - metabolism ; Endoplasmic Reticulum Stress - drug effects ; Enzyme Activation - drug effects ; Humans ; Immunology ; Intracellular Space - metabolism ; Ketones - pharmacology ; Ketones - therapeutic use ; Life Sciences ; Mitogen-Activated Protein Kinases - metabolism ; Models, Biological ; Neoplasms - drug therapy ; Neoplasms - enzymology ; Neoplasms - pathology ; Original ; original-article ; Reproducibility of Results ; Tubulin - metabolism</subject><ispartof>Cell death & disease, 2017-09, Vol.8 (9), p.e3052-e3052</ispartof><rights>The Author(s) 2017</rights><rights>Copyright © 2017 The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c430t-a852a0d5bfd94cfba87cc181a16b72f3014d16ef02f519a69a43081d87a273473</citedby><cites>FETCH-LOGICAL-c430t-a852a0d5bfd94cfba87cc181a16b72f3014d16ef02f519a69a43081d87a273473</cites><orcidid>0000-0002-2837-419X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636972/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5636972/$$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/28906489$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Yan-Jin</creatorcontrib><creatorcontrib>Kumar, Vathan</creatorcontrib><creatorcontrib>Lin, Yuan-Feng</creatorcontrib><creatorcontrib>Liang, Po-Huang</creatorcontrib><title>Disrupting CCT-β : β-tubulin selectively kills CCT-β overexpressed cancer cells through MAPKs activation</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>We have previously demonstrated the ability of I-Trp to disrupt the protein–protein interaction of
β
-tubulin with chaperonin-containing TCP-1
β
(CCT-
β
). This caused more severe apoptosis in multidrug-resistant MES-SA/Dx5, compared to MES-SA, due to its higher CCT-
β
overexpression. In this study, we screened a panel of cancer cell lines, finding CCT-
β
overexpression in the triple-negative breast cancer cell line MDA-MB-231, colorectal cancer cell lines Colo205 and HCT116, and a gastric cancer cell line MKN-45. Thus, I-Trp killed these cancers with sub- to low-
μ
M EC
50
, whereas it was non-toxic to MCF-10A. We then synthesized analogs of I-Trp and evaluated their cytotoxicity. Furthermore, apoptotic mechanism investigations revealed the activation of both protein ubiquitination/degradation and ER-associated protein degradation pathways. These pathways proceeded through activation of MAPKs at the onset of CCT-
β
:
β
-tubulin complex disruption. We thus establish an effective strategy to treat CCT-
β
overexpressed cancers by disrupting the CCT-
β
:
β
-tubulin complex.</description><subject>13/2</subject><subject>13/31</subject><subject>13/95</subject><subject>14/63</subject><subject>38/89</subject><subject>42/109</subject><subject>631/45/612/1228</subject><subject>631/67/1059</subject><subject>631/80/82/23</subject><subject>631/80/86</subject><subject>Antibodies</subject><subject>Apoptosis - drug effects</subject><subject>Biochemistry</subject><subject>Calcium - metabolism</subject><subject>Caspases - metabolism</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell Line, Tumor</subject><subject>Chaperonin Containing TCP-1 - metabolism</subject><subject>Endoplasmic Reticulum Stress - drug effects</subject><subject>Enzyme Activation - drug effects</subject><subject>Humans</subject><subject>Immunology</subject><subject>Intracellular Space - metabolism</subject><subject>Ketones - pharmacology</subject><subject>Ketones - therapeutic use</subject><subject>Life Sciences</subject><subject>Mitogen-Activated Protein Kinases - metabolism</subject><subject>Models, Biological</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - enzymology</subject><subject>Neoplasms - pathology</subject><subject>Original</subject><subject>original-article</subject><subject>Reproducibility of Results</subject><subject>Tubulin - metabolism</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNp1kEtOwzAURS0EolXplCHKBpLazs9hgFSFryiCQRlbjuOkLmkS2UlFZ0zZThfSRbASHFqqMsCSZUvv3PukA8A5gg6CLhnxNJXawRCFjof9I9DH0EO2R0h0fPDvgaHWc2iO60LsB6egh0kEA49EfVBdS63aupFlbsXx1N6svz4-L83drO2mTdpClpYWheCNXIpiZb3JotA70qqWQon3WgmtRWpxVnKhLC46opmpqs1n1tP45VFbrIuzRlblGTjJWKHFcPcOwOvtzTS-tyfPdw_xeGJzz4WNzYiPGUz9JEsjj2cJIyHniCCGgiTEmQuRl6JAZBBnPopYEDETIyglIcOh64XuAFxte-s2WYiUi7JRrKC1kgumVrRikv6dlHJG82pJ_cANohCbAmdbwFWltRLZPosg7ezTH_u0s0-NfRO4ONy4x39dG2C0BbQZlblQdF61qjQW_qv8Bk_flyE</recordid><startdate>20170914</startdate><enddate>20170914</enddate><creator>Liu, Yan-Jin</creator><creator>Kumar, Vathan</creator><creator>Lin, Yuan-Feng</creator><creator>Liang, Po-Huang</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>5PM</scope><orcidid>https://orcid.org/0000-0002-2837-419X</orcidid></search><sort><creationdate>20170914</creationdate><title>Disrupting CCT-β : β-tubulin selectively kills CCT-β overexpressed cancer cells through MAPKs activation</title><author>Liu, Yan-Jin ; Kumar, Vathan ; Lin, Yuan-Feng ; Liang, Po-Huang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c430t-a852a0d5bfd94cfba87cc181a16b72f3014d16ef02f519a69a43081d87a273473</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>13/2</topic><topic>13/31</topic><topic>13/95</topic><topic>14/63</topic><topic>38/89</topic><topic>42/109</topic><topic>631/45/612/1228</topic><topic>631/67/1059</topic><topic>631/80/82/23</topic><topic>631/80/86</topic><topic>Antibodies</topic><topic>Apoptosis - drug effects</topic><topic>Biochemistry</topic><topic>Calcium - metabolism</topic><topic>Caspases - metabolism</topic><topic>Cell Biology</topic><topic>Cell Culture</topic><topic>Cell Line, Tumor</topic><topic>Chaperonin Containing TCP-1 - metabolism</topic><topic>Endoplasmic Reticulum Stress - drug effects</topic><topic>Enzyme Activation - drug effects</topic><topic>Humans</topic><topic>Immunology</topic><topic>Intracellular Space - metabolism</topic><topic>Ketones - pharmacology</topic><topic>Ketones - therapeutic use</topic><topic>Life Sciences</topic><topic>Mitogen-Activated Protein Kinases - metabolism</topic><topic>Models, Biological</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - enzymology</topic><topic>Neoplasms - pathology</topic><topic>Original</topic><topic>original-article</topic><topic>Reproducibility of Results</topic><topic>Tubulin - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Yan-Jin</creatorcontrib><creatorcontrib>Kumar, Vathan</creatorcontrib><creatorcontrib>Lin, Yuan-Feng</creatorcontrib><creatorcontrib>Liang, Po-Huang</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>PubMed Central (Full Participant titles)</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Yan-Jin</au><au>Kumar, Vathan</au><au>Lin, Yuan-Feng</au><au>Liang, Po-Huang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Disrupting CCT-β : β-tubulin selectively kills CCT-β overexpressed cancer cells through MAPKs activation</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2017-09-14</date><risdate>2017</risdate><volume>8</volume><issue>9</issue><spage>e3052</spage><epage>e3052</epage><pages>e3052-e3052</pages><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>We have previously demonstrated the ability of I-Trp to disrupt the protein–protein interaction of
β
-tubulin with chaperonin-containing TCP-1
β
(CCT-
β
). This caused more severe apoptosis in multidrug-resistant MES-SA/Dx5, compared to MES-SA, due to its higher CCT-
β
overexpression. In this study, we screened a panel of cancer cell lines, finding CCT-
β
overexpression in the triple-negative breast cancer cell line MDA-MB-231, colorectal cancer cell lines Colo205 and HCT116, and a gastric cancer cell line MKN-45. Thus, I-Trp killed these cancers with sub- to low-
μ
M EC
50
, whereas it was non-toxic to MCF-10A. We then synthesized analogs of I-Trp and evaluated their cytotoxicity. Furthermore, apoptotic mechanism investigations revealed the activation of both protein ubiquitination/degradation and ER-associated protein degradation pathways. These pathways proceeded through activation of MAPKs at the onset of CCT-
β
:
β
-tubulin complex disruption. We thus establish an effective strategy to treat CCT-
β
overexpressed cancers by disrupting the CCT-
β
:
β
-tubulin complex.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28906489</pmid><doi>10.1038/cddis.2017.425</doi><orcidid>https://orcid.org/0000-0002-2837-419X</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2041-4889 |
| ispartof | Cell death & disease, 2017-09, Vol.8 (9), p.e3052-e3052 |
| issn | 2041-4889 2041-4889 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5636972 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Springer Nature OA Free Journals; Nature Free; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | 13/2 13/31 13/95 14/63 38/89 42/109 631/45/612/1228 631/67/1059 631/80/82/23 631/80/86 Antibodies Apoptosis - drug effects Biochemistry Calcium - metabolism Caspases - metabolism Cell Biology Cell Culture Cell Line, Tumor Chaperonin Containing TCP-1 - metabolism Endoplasmic Reticulum Stress - drug effects Enzyme Activation - drug effects Humans Immunology Intracellular Space - metabolism Ketones - pharmacology Ketones - therapeutic use Life Sciences Mitogen-Activated Protein Kinases - metabolism Models, Biological Neoplasms - drug therapy Neoplasms - enzymology Neoplasms - pathology Original original-article Reproducibility of Results Tubulin - metabolism |
| title | Disrupting CCT-β : β-tubulin selectively kills CCT-β overexpressed cancer cells through MAPKs activation |
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