Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization
Beyond synthesizing telomere repeats, the telomerase reverse transcriptase (TERT) also serves multiple other roles supporting cancer growth. Blocking telomerase to drive telomere erosion appears impractical, but TERT's non-canonical activities have yet to be fully explored as cancer targets. He...
Gespeichert in:
| Veröffentlicht in: | Cell chemical biology 2022-10, Vol.29 (10), p.1517-1531.e7 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1531.e7 |
|---|---|
| container_issue | 10 |
| container_start_page | 1517 |
| container_title | Cell chemical biology |
| container_volume | 29 |
| creator | Liu, Yue Betori, Rick C Pagacz, Joanna Frost, Grant B Efimova, Elena V Wu, Ding Wolfgeher, Donald J Bryan, Tracy M Cohen, Scott B Scheidt, Karl A Kron, Stephen J |
| description | Beyond synthesizing telomere repeats, the telomerase reverse transcriptase (TERT) also serves multiple other roles supporting cancer growth. Blocking telomerase to drive telomere erosion appears impractical, but TERT's non-canonical activities have yet to be fully explored as cancer targets. Here, we used an irreversible TERT inhibitor, NU-1, to examine impacts on resistance to conventional cancer therapies. In vitro, inhibiting TERT sensitized cells to chemotherapy and radiation. NU-1 delayed repair of double-strand breaks, resulting in persistent DNA damage signaling and cellular senescence. Although NU-1 alone did not impact growth of syngeneic CT26 tumors in BALB/c mice, it dramatically enhanced the effects of radiation, leading to immune-dependent tumor elimination. Tumors displayed persistent DNA damage, suppressed proliferation, and increased activated immune infiltrate. Our studies confirm TERT's role in limiting genotoxic effects of conventional therapy but also implicate TERT as a determinant of immune evasion and therapy resistance. |
| doi_str_mv | 10.1016/j.chembiol.2022.09.002 |
| format | Article |
| fullrecord | <record><control><sourceid>pubmed_cross</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9588800</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>36206753</sourcerecordid><originalsourceid>FETCH-LOGICAL-c414t-b266fe6d347c3014956b350d8958fb51de5b9795fc24f809f68241e615ce9f2c3</originalsourceid><addsrcrecordid>eNpVkdtq3DAQhkVpaUKaVwh6Abs627oplNAThPYmuRayPFprsaVFUja0T19t0yzt1Zz4_hnmR-iGkp4Sqt7ve7fANoW09oww1hPdE8JeoUsmJO20EOPrcy7VBbouZU9II_lA-fAWXXDFiBokv0RP9zbvoIa4wxXWtEG2BXCGI-QWa7axuBwO9dR9CnXBdQHs0tGuECsOcQlTqCnj7w8dbf3oG4fDtj3GtIMYHM52DraGFHGBWEINv_5U79Abb9cC13_jFXr4_On-9mt39-PLt9uPd50TVNRuYkp5UDMXg-OECi3VxCWZRy1HP0k6g5z0oKV3TPiRaK9GJigoKh1ozxy_Qh-edQ-P0waza1dnu5pDDpvNP02ywfw_iWExu3Q0bcE4EtIE1LOAy6mUDP7MUmJObpi9eXHDnNwwRJvmRgNv_t18xl5-z38DobSNVQ</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization</title><source>MEDLINE</source><source>Cell Press Free Archives</source><source>EZB-FREE-00999 freely available EZB journals</source><source>Alma/SFX Local Collection</source><source>Free Full-Text Journals in Chemistry</source><creator>Liu, Yue ; Betori, Rick C ; Pagacz, Joanna ; Frost, Grant B ; Efimova, Elena V ; Wu, Ding ; Wolfgeher, Donald J ; Bryan, Tracy M ; Cohen, Scott B ; Scheidt, Karl A ; Kron, Stephen J</creator><creatorcontrib>Liu, Yue ; Betori, Rick C ; Pagacz, Joanna ; Frost, Grant B ; Efimova, Elena V ; Wu, Ding ; Wolfgeher, Donald J ; Bryan, Tracy M ; Cohen, Scott B ; Scheidt, Karl A ; Kron, Stephen J</creatorcontrib><description>Beyond synthesizing telomere repeats, the telomerase reverse transcriptase (TERT) also serves multiple other roles supporting cancer growth. Blocking telomerase to drive telomere erosion appears impractical, but TERT's non-canonical activities have yet to be fully explored as cancer targets. Here, we used an irreversible TERT inhibitor, NU-1, to examine impacts on resistance to conventional cancer therapies. In vitro, inhibiting TERT sensitized cells to chemotherapy and radiation. NU-1 delayed repair of double-strand breaks, resulting in persistent DNA damage signaling and cellular senescence. Although NU-1 alone did not impact growth of syngeneic CT26 tumors in BALB/c mice, it dramatically enhanced the effects of radiation, leading to immune-dependent tumor elimination. Tumors displayed persistent DNA damage, suppressed proliferation, and increased activated immune infiltrate. Our studies confirm TERT's role in limiting genotoxic effects of conventional therapy but also implicate TERT as a determinant of immune evasion and therapy resistance.</description><identifier>ISSN: 2451-9456</identifier><identifier>EISSN: 2451-9448</identifier><identifier>EISSN: 2451-9456</identifier><identifier>DOI: 10.1016/j.chembiol.2022.09.002</identifier><identifier>PMID: 36206753</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Cellular Senescence - drug effects ; DNA Damage - drug effects ; Mice ; Radiation Tolerance - drug effects ; Telomerase - antagonists & inhibitors ; Telomerase - metabolism ; Telomere</subject><ispartof>Cell chemical biology, 2022-10, Vol.29 (10), p.1517-1531.e7</ispartof><rights>Copyright © 2022 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c414t-b266fe6d347c3014956b350d8958fb51de5b9795fc24f809f68241e615ce9f2c3</citedby><cites>FETCH-LOGICAL-c414t-b266fe6d347c3014956b350d8958fb51de5b9795fc24f809f68241e615ce9f2c3</cites><orcidid>0000-0002-8344-9756 ; 0000-0003-1518-2436</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36206753$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Yue</creatorcontrib><creatorcontrib>Betori, Rick C</creatorcontrib><creatorcontrib>Pagacz, Joanna</creatorcontrib><creatorcontrib>Frost, Grant B</creatorcontrib><creatorcontrib>Efimova, Elena V</creatorcontrib><creatorcontrib>Wu, Ding</creatorcontrib><creatorcontrib>Wolfgeher, Donald J</creatorcontrib><creatorcontrib>Bryan, Tracy M</creatorcontrib><creatorcontrib>Cohen, Scott B</creatorcontrib><creatorcontrib>Scheidt, Karl A</creatorcontrib><creatorcontrib>Kron, Stephen J</creatorcontrib><title>Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization</title><title>Cell chemical biology</title><addtitle>Cell Chem Biol</addtitle><description>Beyond synthesizing telomere repeats, the telomerase reverse transcriptase (TERT) also serves multiple other roles supporting cancer growth. Blocking telomerase to drive telomere erosion appears impractical, but TERT's non-canonical activities have yet to be fully explored as cancer targets. Here, we used an irreversible TERT inhibitor, NU-1, to examine impacts on resistance to conventional cancer therapies. In vitro, inhibiting TERT sensitized cells to chemotherapy and radiation. NU-1 delayed repair of double-strand breaks, resulting in persistent DNA damage signaling and cellular senescence. Although NU-1 alone did not impact growth of syngeneic CT26 tumors in BALB/c mice, it dramatically enhanced the effects of radiation, leading to immune-dependent tumor elimination. Tumors displayed persistent DNA damage, suppressed proliferation, and increased activated immune infiltrate. Our studies confirm TERT's role in limiting genotoxic effects of conventional therapy but also implicate TERT as a determinant of immune evasion and therapy resistance.</description><subject>Animals</subject><subject>Cellular Senescence - drug effects</subject><subject>DNA Damage - drug effects</subject><subject>Mice</subject><subject>Radiation Tolerance - drug effects</subject><subject>Telomerase - antagonists & inhibitors</subject><subject>Telomerase - metabolism</subject><subject>Telomere</subject><issn>2451-9456</issn><issn>2451-9448</issn><issn>2451-9456</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkdtq3DAQhkVpaUKaVwh6Abs627oplNAThPYmuRayPFprsaVFUja0T19t0yzt1Zz4_hnmR-iGkp4Sqt7ve7fANoW09oww1hPdE8JeoUsmJO20EOPrcy7VBbouZU9II_lA-fAWXXDFiBokv0RP9zbvoIa4wxXWtEG2BXCGI-QWa7axuBwO9dR9CnXBdQHs0tGuECsOcQlTqCnj7w8dbf3oG4fDtj3GtIMYHM52DraGFHGBWEINv_5U79Abb9cC13_jFXr4_On-9mt39-PLt9uPd50TVNRuYkp5UDMXg-OECi3VxCWZRy1HP0k6g5z0oKV3TPiRaK9GJigoKh1ozxy_Qh-edQ-P0waza1dnu5pDDpvNP02ywfw_iWExu3Q0bcE4EtIE1LOAy6mUDP7MUmJObpi9eXHDnNwwRJvmRgNv_t18xl5-z38DobSNVQ</recordid><startdate>20221020</startdate><enddate>20221020</enddate><creator>Liu, Yue</creator><creator>Betori, Rick C</creator><creator>Pagacz, Joanna</creator><creator>Frost, Grant B</creator><creator>Efimova, Elena V</creator><creator>Wu, Ding</creator><creator>Wolfgeher, Donald J</creator><creator>Bryan, Tracy M</creator><creator>Cohen, Scott B</creator><creator>Scheidt, Karl A</creator><creator>Kron, Stephen J</creator><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/0000-0002-8344-9756</orcidid><orcidid>https://orcid.org/0000-0003-1518-2436</orcidid></search><sort><creationdate>20221020</creationdate><title>Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization</title><author>Liu, Yue ; Betori, Rick C ; Pagacz, Joanna ; Frost, Grant B ; Efimova, Elena V ; Wu, Ding ; Wolfgeher, Donald J ; Bryan, Tracy M ; Cohen, Scott B ; Scheidt, Karl A ; Kron, Stephen J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c414t-b266fe6d347c3014956b350d8958fb51de5b9795fc24f809f68241e615ce9f2c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Cellular Senescence - drug effects</topic><topic>DNA Damage - drug effects</topic><topic>Mice</topic><topic>Radiation Tolerance - drug effects</topic><topic>Telomerase - antagonists & inhibitors</topic><topic>Telomerase - metabolism</topic><topic>Telomere</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Yue</creatorcontrib><creatorcontrib>Betori, Rick C</creatorcontrib><creatorcontrib>Pagacz, Joanna</creatorcontrib><creatorcontrib>Frost, Grant B</creatorcontrib><creatorcontrib>Efimova, Elena V</creatorcontrib><creatorcontrib>Wu, Ding</creatorcontrib><creatorcontrib>Wolfgeher, Donald J</creatorcontrib><creatorcontrib>Bryan, Tracy M</creatorcontrib><creatorcontrib>Cohen, Scott B</creatorcontrib><creatorcontrib>Scheidt, Karl A</creatorcontrib><creatorcontrib>Kron, Stephen J</creatorcontrib><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 chemical biology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Yue</au><au>Betori, Rick C</au><au>Pagacz, Joanna</au><au>Frost, Grant B</au><au>Efimova, Elena V</au><au>Wu, Ding</au><au>Wolfgeher, Donald J</au><au>Bryan, Tracy M</au><au>Cohen, Scott B</au><au>Scheidt, Karl A</au><au>Kron, Stephen J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization</atitle><jtitle>Cell chemical biology</jtitle><addtitle>Cell Chem Biol</addtitle><date>2022-10-20</date><risdate>2022</risdate><volume>29</volume><issue>10</issue><spage>1517</spage><epage>1531.e7</epage><pages>1517-1531.e7</pages><issn>2451-9456</issn><eissn>2451-9448</eissn><eissn>2451-9456</eissn><abstract>Beyond synthesizing telomere repeats, the telomerase reverse transcriptase (TERT) also serves multiple other roles supporting cancer growth. Blocking telomerase to drive telomere erosion appears impractical, but TERT's non-canonical activities have yet to be fully explored as cancer targets. Here, we used an irreversible TERT inhibitor, NU-1, to examine impacts on resistance to conventional cancer therapies. In vitro, inhibiting TERT sensitized cells to chemotherapy and radiation. NU-1 delayed repair of double-strand breaks, resulting in persistent DNA damage signaling and cellular senescence. Although NU-1 alone did not impact growth of syngeneic CT26 tumors in BALB/c mice, it dramatically enhanced the effects of radiation, leading to immune-dependent tumor elimination. Tumors displayed persistent DNA damage, suppressed proliferation, and increased activated immune infiltrate. Our studies confirm TERT's role in limiting genotoxic effects of conventional therapy but also implicate TERT as a determinant of immune evasion and therapy resistance.</abstract><cop>United States</cop><pmid>36206753</pmid><doi>10.1016/j.chembiol.2022.09.002</doi><orcidid>https://orcid.org/0000-0002-8344-9756</orcidid><orcidid>https://orcid.org/0000-0003-1518-2436</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2451-9456 |
| ispartof | Cell chemical biology, 2022-10, Vol.29 (10), p.1517-1531.e7 |
| issn | 2451-9456 2451-9448 2451-9456 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_9588800 |
| source | MEDLINE; Cell Press Free Archives; EZB-FREE-00999 freely available EZB journals; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Animals Cellular Senescence - drug effects DNA Damage - drug effects Mice Radiation Tolerance - drug effects Telomerase - antagonists & inhibitors Telomerase - metabolism Telomere |
| title | Targeting telomerase reverse transcriptase with the covalent inhibitor NU-1 confers immunogenic radiation sensitization |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T08%3A04%3A48IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Targeting%20telomerase%20reverse%20transcriptase%20with%20the%20covalent%20inhibitor%20NU-1%20confers%20immunogenic%20radiation%20sensitization&rft.jtitle=Cell%20chemical%20biology&rft.au=Liu,%20Yue&rft.date=2022-10-20&rft.volume=29&rft.issue=10&rft.spage=1517&rft.epage=1531.e7&rft.pages=1517-1531.e7&rft.issn=2451-9456&rft.eissn=2451-9448&rft_id=info:doi/10.1016/j.chembiol.2022.09.002&rft_dat=%3Cpubmed_cross%3E36206753%3C/pubmed_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/36206753&rfr_iscdi=true |