Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells
We have defined the mechanism of action of lurbinectedin, a marine-derived drug exhibiting a potent antitumor activity across several cancer cell lines and tumor xenografts. This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the tran...
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| Veröffentlicht in: | Molecular cancer therapeutics 2016-10, Vol.15 (10), p.2399-2412 |
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| container_title | Molecular cancer therapeutics |
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| creator | Santamaría Nuñez, Gema Robles, Carlos Mario Genes Giraudon, Christophe Martínez-Leal, Juan Fernando Compe, Emmanuel Coin, Frédéric Aviles, Pablo Galmarini, Carlos María Egly, Jean-Marc |
| description | We have defined the mechanism of action of lurbinectedin, a marine-derived drug exhibiting a potent antitumor activity across several cancer cell lines and tumor xenografts. This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis. The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair. Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism. Mol Cancer Ther; 15(10); 2399-412. ©2016 AACR. |
| doi_str_mv | 10.1158/1535-7163.mct-16-0172 |
| format | Article |
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This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis. The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair. Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism. 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This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis. The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair. Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism. Mol Cancer Ther; 15(10); 2399-412. ©2016 AACR.</description><subject>Animals</subject><subject>Antineoplastic Agents - chemistry</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Aquatic Organisms - chemistry</subject><subject>Biological Products - chemistry</subject><subject>Biological Products - pharmacology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Disease Models, Animal</subject><subject>DNA Breaks</subject><subject>Female</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Mice</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - genetics</subject><subject>Neoplasms - metabolism</subject><subject>Neoplasms - pathology</subject><subject>Phosphorylation</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Protein Binding</subject><subject>Proteolysis</subject><subject>RNA Polymerase II - metabolism</subject><subject>Transcription, Genetic</subject><subject>Transcriptional Activation</subject><subject>Ubiquitin - metabolism</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kdFu0zAUhi0EYmPwCCBfwkWGTxzHzmXJNlapbBOUa-vEdlpDEhc7ndQn4LVJ1tErW0ff_58jfYS8B3YJINRnEFxkEkp-2ZsxgzJjIPMX5Hyaq0wJKF4-_Y_MGXmT0i_GQFU5vCZnuSw5yyWck7-rfWz84MzorB_oj50zvvUGu-5A19FvNi4mOm4dvXKbiBZHHwYaWvqwDWm3DfHQ4ZSk3-8W9CF0h95FTI4ulxQH-5S7CbE_pa4m7Et0-DvRaVmNg3GR1q7r0lvyqsUuuXfP7wX5eXO9rm-z1f3XZb1YZUYwNWa2AF4WaAGckIKhsrY0pUWUuVAgDBR5zltZOcGrRqFsK6u4VKq1FTaNafkF-XTs3WKnd9H3GA86oNe3i5WeZ4yLqaMsHmFiPx7ZXQx_9i6NuvfJTNfi4MI-aVBccMmqik-oOKImhpSia0_dwPTsS88u9OxCf6vXGko9-5pyH55X7Jve2VPqvyD-D04xkVc</recordid><startdate>20161001</startdate><enddate>20161001</enddate><creator>Santamaría Nuñez, Gema</creator><creator>Robles, Carlos Mario Genes</creator><creator>Giraudon, Christophe</creator><creator>Martínez-Leal, Juan Fernando</creator><creator>Compe, Emmanuel</creator><creator>Coin, Frédéric</creator><creator>Aviles, Pablo</creator><creator>Galmarini, Carlos María</creator><creator>Egly, Jean-Marc</creator><general>American Association for Cancer Research</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>7X8</scope><scope>1XC</scope><orcidid>https://orcid.org/0000-0002-5620-8519</orcidid></search><sort><creationdate>20161001</creationdate><title>Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells</title><author>Santamaría Nuñez, Gema ; 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This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis. The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair. Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism. 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| subjects | Animals Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Aquatic Organisms - chemistry Biological Products - chemistry Biological Products - pharmacology Cell Line, Tumor Cell Proliferation - drug effects Disease Models, Animal DNA Breaks Female Humans Life Sciences Mice Neoplasms - drug therapy Neoplasms - genetics Neoplasms - metabolism Neoplasms - pathology Phosphorylation Proteasome Endopeptidase Complex - metabolism Protein Binding Proteolysis RNA Polymerase II - metabolism Transcription, Genetic Transcriptional Activation Ubiquitin - metabolism Xenograft Model Antitumor Assays |
| title | Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells |
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