Decreased mitochondrial priming determines chemoresistance of colon cancer stem cells
Tumor heterogeneity is in part determined by the existence of cancer stem cells (CSCs) and more differentiated tumor cells. CSCs are considered to be the tumorigenic root of cancers and suggested to be chemotherapy resistant. Here we exploited an assay that allowed us to measure chemotherapy-induced...
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| Veröffentlicht in: | Cell death and differentiation 2014-07, Vol.21 (7), p.1170-1177 |
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| creator | Colak, S Zimberlin, C D Fessler, E Hogdal, L Prasetyanti, P R Grandela, C M Letai, A Medema, J P |
| description | Tumor heterogeneity is in part determined by the existence of cancer stem cells (CSCs) and more differentiated tumor cells. CSCs are considered to be the tumorigenic root of cancers and suggested to be chemotherapy resistant. Here we exploited an assay that allowed us to measure chemotherapy-induced cell death in CSCs and differentiated tumor cells simultaneously. This confirmed that CSCs are selectively resistant to conventional chemotherapy, which we revealed is determined by decreased mitochondrial priming. In agreement, lowering the anti-apoptotic threshold using ABT-737 and WEHI-539 was sufficient to enhance chemotherapy efficacy, whereas ABT-199 failed to sensitize CSCs. Our data therefore point to a crucial role of BCLXL in protecting CSCs from chemotherapy and suggest that BH3 mimetics, in combination with chemotherapy, can be an efficient way to target chemotherapy-resistant CSCs. |
| doi_str_mv | 10.1038/cdd.2014.37 |
| format | Article |
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CSCs are considered to be the tumorigenic root of cancers and suggested to be chemotherapy resistant. Here we exploited an assay that allowed us to measure chemotherapy-induced cell death in CSCs and differentiated tumor cells simultaneously. This confirmed that CSCs are selectively resistant to conventional chemotherapy, which we revealed is determined by decreased mitochondrial priming. In agreement, lowering the anti-apoptotic threshold using ABT-737 and WEHI-539 was sufficient to enhance chemotherapy efficacy, whereas ABT-199 failed to sensitize CSCs. Our data therefore point to a crucial role of BCLXL in protecting CSCs from chemotherapy and suggest that BH3 mimetics, in combination with chemotherapy, can be an efficient way to target chemotherapy-resistant CSCs.</description><identifier>ISSN: 1350-9047</identifier><identifier>EISSN: 1476-5403</identifier><identifier>DOI: 10.1038/cdd.2014.37</identifier><identifier>PMID: 24682005</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/67/1059/2326 ; 631/67/1059/99 ; 631/67/1504/1885/1393 ; 631/80/82/23 ; Antineoplastic Agents - pharmacology ; Apoptosis ; bcl-X Protein - antagonists & inhibitors ; Biochemistry ; Biomedical and Life Sciences ; Cancer therapies ; Cell Biology ; Cell Cycle Analysis ; Cell death ; Cell Survival ; Chemotherapy ; Colonic Neoplasms - drug therapy ; Colonic Neoplasms - pathology ; Colorectal cancer ; Drug Resistance, Neoplasm ; Humans ; Leukemia ; Life Sciences ; Lymphoma ; Mitochondria - metabolism ; Neoplastic Stem Cells - drug effects ; Neoplastic Stem Cells - physiology ; Oncology ; Original Paper ; Proteins ; Stem Cells ; Tumor Cells, Cultured ; Tumors</subject><ispartof>Cell death and differentiation, 2014-07, Vol.21 (7), p.1170-1177</ispartof><rights>Macmillan Publishers Limited 2014</rights><rights>Copyright Nature Publishing Group Jul 2014</rights><rights>Copyright © 2014 Macmillan Publishers Limited 2014 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c446t-4f9c5c4bce5a2067e7d105d0c8708358f2b765bd5f935a34196f9a6456a3b3e33</citedby><cites>FETCH-LOGICAL-c446t-4f9c5c4bce5a2067e7d105d0c8708358f2b765bd5f935a34196f9a6456a3b3e33</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/PMC4207483/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207483/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,41467,42536,51297,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24682005$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Colak, S</creatorcontrib><creatorcontrib>Zimberlin, C D</creatorcontrib><creatorcontrib>Fessler, E</creatorcontrib><creatorcontrib>Hogdal, L</creatorcontrib><creatorcontrib>Prasetyanti, P R</creatorcontrib><creatorcontrib>Grandela, C M</creatorcontrib><creatorcontrib>Letai, A</creatorcontrib><creatorcontrib>Medema, J P</creatorcontrib><title>Decreased mitochondrial priming determines chemoresistance of colon cancer stem cells</title><title>Cell death and differentiation</title><addtitle>Cell Death Differ</addtitle><addtitle>Cell Death Differ</addtitle><description>Tumor heterogeneity is in part determined by the existence of cancer stem cells (CSCs) and more differentiated tumor cells. CSCs are considered to be the tumorigenic root of cancers and suggested to be chemotherapy resistant. Here we exploited an assay that allowed us to measure chemotherapy-induced cell death in CSCs and differentiated tumor cells simultaneously. This confirmed that CSCs are selectively resistant to conventional chemotherapy, which we revealed is determined by decreased mitochondrial priming. In agreement, lowering the anti-apoptotic threshold using ABT-737 and WEHI-539 was sufficient to enhance chemotherapy efficacy, whereas ABT-199 failed to sensitize CSCs. 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metabolism</subject><subject>Neoplastic Stem Cells - drug effects</subject><subject>Neoplastic Stem Cells - physiology</subject><subject>Oncology</subject><subject>Original Paper</subject><subject>Proteins</subject><subject>Stem Cells</subject><subject>Tumor Cells, Cultured</subject><subject>Tumors</subject><issn>1350-9047</issn><issn>1476-5403</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNptkc1P3DAQxa2Kqku3PXGvLHFBgix2_JVckBC0UGmlXsrZcuzJblBib-0sUv97HBbQgjh5rPnpzZt5CB1RsqCEVefWuUVJKF8w9QkdUq5kIThhB7lmghQ14WqGvqZ0TwiRqpZf0KzksioJEYfo7hpsBJPA4aEbg10H72JneryJ3dD5FXYwQswVJGzXMIQIqUuj8RZwaLENffDYTt-I0wgDttD36Rv63Jo-wffnd47ufv38e3VbLP_c_L66XBaWczkWvK2tsLyxIEyZvYFylAhHbKVIxUTVlo2SonGirZkwjNNatrWRXEjDGgaMzdHFTnezbQZwFvwYTa8n7yb-18F0-m3Hd2u9Cg-al0TxahI4eRaI4d8W0qiHLk0rGA9hmzQVjHOVrzuhx-_Q-7CNPq_3RFFKyxzHHJ3uKBtDShHaVzOU6CkunePSU1yaqUz_2Pf_yr7kk4GzHZByy68g7g39QO8RDQ6f_Q</recordid><startdate>20140701</startdate><enddate>20140701</enddate><creator>Colak, S</creator><creator>Zimberlin, C D</creator><creator>Fessler, E</creator><creator>Hogdal, L</creator><creator>Prasetyanti, P R</creator><creator>Grandela, C M</creator><creator>Letai, A</creator><creator>Medema, J P</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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><scope>3V.</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</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>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140701</creationdate><title>Decreased mitochondrial priming determines chemoresistance of colon cancer stem cells</title><author>Colak, S ; Zimberlin, C D ; Fessler, E ; Hogdal, L ; Prasetyanti, P R ; Grandela, C M ; Letai, A ; Medema, J P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c446t-4f9c5c4bce5a2067e7d105d0c8708358f2b765bd5f935a34196f9a6456a3b3e33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>631/67/1059/2326</topic><topic>631/67/1059/99</topic><topic>631/67/1504/1885/1393</topic><topic>631/80/82/23</topic><topic>Antineoplastic Agents - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death and differentiation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Colak, S</au><au>Zimberlin, C D</au><au>Fessler, E</au><au>Hogdal, L</au><au>Prasetyanti, P R</au><au>Grandela, C M</au><au>Letai, A</au><au>Medema, J P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Decreased mitochondrial priming determines chemoresistance of colon cancer stem cells</atitle><jtitle>Cell death and differentiation</jtitle><stitle>Cell Death Differ</stitle><addtitle>Cell Death Differ</addtitle><date>2014-07-01</date><risdate>2014</risdate><volume>21</volume><issue>7</issue><spage>1170</spage><epage>1177</epage><pages>1170-1177</pages><issn>1350-9047</issn><eissn>1476-5403</eissn><abstract>Tumor heterogeneity is in part determined by the existence of cancer stem cells (CSCs) and more differentiated tumor cells. 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| subjects | 631/67/1059/2326 631/67/1059/99 631/67/1504/1885/1393 631/80/82/23 Antineoplastic Agents - pharmacology Apoptosis bcl-X Protein - antagonists & inhibitors Biochemistry Biomedical and Life Sciences Cancer therapies Cell Biology Cell Cycle Analysis Cell death Cell Survival Chemotherapy Colonic Neoplasms - drug therapy Colonic Neoplasms - pathology Colorectal cancer Drug Resistance, Neoplasm Humans Leukemia Life Sciences Lymphoma Mitochondria - metabolism Neoplastic Stem Cells - drug effects Neoplastic Stem Cells - physiology Oncology Original Paper Proteins Stem Cells Tumor Cells, Cultured Tumors |
| title | Decreased mitochondrial priming determines chemoresistance of colon cancer stem cells |
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