Oncogenic mutant KRAS inhibition through oxidation at cysteine 118

Oncogenic mutant KRAS inhibition through oxidation at cysteine 118

Specific reactive oxygen species activate the GTPase Kirsten rat sarcoma virus (KRAS) by reacting with cysteine 118 (C118), leading to an electron transfer between C118 and nucleoside guanosine diphosphate (GDP), which causes the release of GDP. Here, we have mimicked permanent oxidation of human KR...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Molecular oncology 2025-01
Hauptverfasser: Kramer-Drauberg, Maximilian, Petrini, Ettore, Mira, Alessia, Patrucco, Enrico, Scardaci, Rossella, Savinelli, Ilenia, Wang, Haiyun, Qiao, Keying, Carrà, Giovanna, Nokin, Marie-Julie, Zhou, Zhiwei, Westover, Kenneth D, Santamaria, David, Porporato, Paolo E, Ambrogio, Chiara
Format: Artikel
Sprache:eng
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
container_end_page
container_issue
container_start_page
container_title Molecular oncology
container_volume
creator Kramer-Drauberg, Maximilian
Petrini, Ettore
Mira, Alessia
Patrucco, Enrico
Scardaci, Rossella
Savinelli, Ilenia
Wang, Haiyun
Qiao, Keying
Carrà, Giovanna
Nokin, Marie-Julie
Zhou, Zhiwei
Westover, Kenneth D
Santamaria, David
Porporato, Paolo E
Ambrogio, Chiara
description Specific reactive oxygen species activate the GTPase Kirsten rat sarcoma virus (KRAS) by reacting with cysteine 118 (C118), leading to an electron transfer between C118 and nucleoside guanosine diphosphate (GDP), which causes the release of GDP. Here, we have mimicked permanent oxidation of human KRAS at C118 by replacing C118 with aspartic acid (C118D) in KRAS to show that oncogenic mutant KRAS is selectively inhibited via oxidation at C118, both in vitro and in vivo. Moreover, the combined treatment of hydrogen-peroxide-producing pro-oxidant paraquat and nitric-oxide-producing inhibitor N(ω)-nitro-l-arginine methyl ester selectively inhibits human mutant KRAS activity by inducing oxidization at C118. Our study shows for the first time the vulnerability of human mutant KRAS to oxidation, thereby paving the way to explore oxidation-based anti-KRAS treatments in humans.
doi_str_mv 10.1002/1878-0261.13798
format Article
fullrecord <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3158101018</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3158101018</sourcerecordid><originalsourceid>FETCH-LOGICAL-c1378-3024ef818371e7e2f08f45832bd8de535f60e8cf90b970cad6d66c474027552c3</originalsourceid><addsrcrecordid>eNo9kEtPwzAQhC0EoqVw5oZy5JLWjmN7fSwVL1GpEo-z5Th2a9Q4JU4k-u9JH1R72NVodjT6ELoleEwwziYEBKQ442RMqJBwhoYn5by_mchTAZIM0FWM3xgzLrm8RAMqgQIQPkQPi2DqpQ3eJFXX6tAmb-_Tj8SHlS986-uQtKum7parpP71pd4ruk3MNrbWB5sQAtfowul1tDfHPUJfT4-fs5d0vnh-nU3nqem7QUpxllsHBKggVtjMYXA5A5oVJZSWUeY4tmCcxIUU2OiSl5ybXOQ4E4xlho7Q_SF309Q_nY2tqnw0dr3WwdZdVJQwILgf6K2Tg9U0dYyNdWrT-Eo3W0Ww2oFTO0xqh0ntwfUfd8fwrqhsefL_k6J_mahmZg</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3158101018</pqid></control><display><type>article</type><title>Oncogenic mutant KRAS inhibition through oxidation at cysteine 118</title><source>Wiley Online Library</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Wiley Open Access</source><source>PubMed Central</source><source>Directory of Open Access Journals</source><creator>Kramer-Drauberg, Maximilian ; Petrini, Ettore ; Mira, Alessia ; Patrucco, Enrico ; Scardaci, Rossella ; Savinelli, Ilenia ; Wang, Haiyun ; Qiao, Keying ; Carrà, Giovanna ; Nokin, Marie-Julie ; Zhou, Zhiwei ; Westover, Kenneth D ; Santamaria, David ; Porporato, Paolo E ; Ambrogio, Chiara</creator><creatorcontrib>Kramer-Drauberg, Maximilian ; Petrini, Ettore ; Mira, Alessia ; Patrucco, Enrico ; Scardaci, Rossella ; Savinelli, Ilenia ; Wang, Haiyun ; Qiao, Keying ; Carrà, Giovanna ; Nokin, Marie-Julie ; Zhou, Zhiwei ; Westover, Kenneth D ; Santamaria, David ; Porporato, Paolo E ; Ambrogio, Chiara</creatorcontrib><description>Specific reactive oxygen species activate the GTPase Kirsten rat sarcoma virus (KRAS) by reacting with cysteine 118 (C118), leading to an electron transfer between C118 and nucleoside guanosine diphosphate (GDP), which causes the release of GDP. Here, we have mimicked permanent oxidation of human KRAS at C118 by replacing C118 with aspartic acid (C118D) in KRAS to show that oncogenic mutant KRAS is selectively inhibited via oxidation at C118, both in vitro and in vivo. Moreover, the combined treatment of hydrogen-peroxide-producing pro-oxidant paraquat and nitric-oxide-producing inhibitor N(ω)-nitro-l-arginine methyl ester selectively inhibits human mutant KRAS activity by inducing oxidization at C118. Our study shows for the first time the vulnerability of human mutant KRAS to oxidation, thereby paving the way to explore oxidation-based anti-KRAS treatments in humans.</description><identifier>ISSN: 1574-7891</identifier><identifier>ISSN: 1878-0261</identifier><identifier>EISSN: 1878-0261</identifier><identifier>DOI: 10.1002/1878-0261.13798</identifier><identifier>PMID: 39838816</identifier><language>eng</language><publisher>United States</publisher><ispartof>Molecular oncology, 2025-01</ispartof><rights>2025 The Author(s). Molecular Oncology published by John Wiley &amp; Sons Ltd on behalf of Federation of European Biochemical Societies.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c1378-3024ef818371e7e2f08f45832bd8de535f60e8cf90b970cad6d66c474027552c3</cites><orcidid>0000-0001-8519-1552 ; 0000-0003-4122-701X ; 0000-0002-6263-6800</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,860,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39838816$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kramer-Drauberg, Maximilian</creatorcontrib><creatorcontrib>Petrini, Ettore</creatorcontrib><creatorcontrib>Mira, Alessia</creatorcontrib><creatorcontrib>Patrucco, Enrico</creatorcontrib><creatorcontrib>Scardaci, Rossella</creatorcontrib><creatorcontrib>Savinelli, Ilenia</creatorcontrib><creatorcontrib>Wang, Haiyun</creatorcontrib><creatorcontrib>Qiao, Keying</creatorcontrib><creatorcontrib>Carrà, Giovanna</creatorcontrib><creatorcontrib>Nokin, Marie-Julie</creatorcontrib><creatorcontrib>Zhou, Zhiwei</creatorcontrib><creatorcontrib>Westover, Kenneth D</creatorcontrib><creatorcontrib>Santamaria, David</creatorcontrib><creatorcontrib>Porporato, Paolo E</creatorcontrib><creatorcontrib>Ambrogio, Chiara</creatorcontrib><title>Oncogenic mutant KRAS inhibition through oxidation at cysteine 118</title><title>Molecular oncology</title><addtitle>Mol Oncol</addtitle><description>Specific reactive oxygen species activate the GTPase Kirsten rat sarcoma virus (KRAS) by reacting with cysteine 118 (C118), leading to an electron transfer between C118 and nucleoside guanosine diphosphate (GDP), which causes the release of GDP. Here, we have mimicked permanent oxidation of human KRAS at C118 by replacing C118 with aspartic acid (C118D) in KRAS to show that oncogenic mutant KRAS is selectively inhibited via oxidation at C118, both in vitro and in vivo. Moreover, the combined treatment of hydrogen-peroxide-producing pro-oxidant paraquat and nitric-oxide-producing inhibitor N(ω)-nitro-l-arginine methyl ester selectively inhibits human mutant KRAS activity by inducing oxidization at C118. Our study shows for the first time the vulnerability of human mutant KRAS to oxidation, thereby paving the way to explore oxidation-based anti-KRAS treatments in humans.</description><issn>1574-7891</issn><issn>1878-0261</issn><issn>1878-0261</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2025</creationdate><recordtype>article</recordtype><recordid>eNo9kEtPwzAQhC0EoqVw5oZy5JLWjmN7fSwVL1GpEo-z5Th2a9Q4JU4k-u9JH1R72NVodjT6ELoleEwwziYEBKQ442RMqJBwhoYn5by_mchTAZIM0FWM3xgzLrm8RAMqgQIQPkQPi2DqpQ3eJFXX6tAmb-_Tj8SHlS986-uQtKum7parpP71pd4ruk3MNrbWB5sQAtfowul1tDfHPUJfT4-fs5d0vnh-nU3nqem7QUpxllsHBKggVtjMYXA5A5oVJZSWUeY4tmCcxIUU2OiSl5ybXOQ4E4xlho7Q_SF309Q_nY2tqnw0dr3WwdZdVJQwILgf6K2Tg9U0dYyNdWrT-Eo3W0Ww2oFTO0xqh0ntwfUfd8fwrqhsefL_k6J_mahmZg</recordid><startdate>20250121</startdate><enddate>20250121</enddate><creator>Kramer-Drauberg, Maximilian</creator><creator>Petrini, Ettore</creator><creator>Mira, Alessia</creator><creator>Patrucco, Enrico</creator><creator>Scardaci, Rossella</creator><creator>Savinelli, Ilenia</creator><creator>Wang, Haiyun</creator><creator>Qiao, Keying</creator><creator>Carrà, Giovanna</creator><creator>Nokin, Marie-Julie</creator><creator>Zhou, Zhiwei</creator><creator>Westover, Kenneth D</creator><creator>Santamaria, David</creator><creator>Porporato, Paolo E</creator><creator>Ambrogio, Chiara</creator><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-8519-1552</orcidid><orcidid>https://orcid.org/0000-0003-4122-701X</orcidid><orcidid>https://orcid.org/0000-0002-6263-6800</orcidid></search><sort><creationdate>20250121</creationdate><title>Oncogenic mutant KRAS inhibition through oxidation at cysteine 118</title><author>Kramer-Drauberg, Maximilian ; Petrini, Ettore ; Mira, Alessia ; Patrucco, Enrico ; Scardaci, Rossella ; Savinelli, Ilenia ; Wang, Haiyun ; Qiao, Keying ; Carrà, Giovanna ; Nokin, Marie-Julie ; Zhou, Zhiwei ; Westover, Kenneth D ; Santamaria, David ; Porporato, Paolo E ; Ambrogio, Chiara</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1378-3024ef818371e7e2f08f45832bd8de535f60e8cf90b970cad6d66c474027552c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2025</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kramer-Drauberg, Maximilian</creatorcontrib><creatorcontrib>Petrini, Ettore</creatorcontrib><creatorcontrib>Mira, Alessia</creatorcontrib><creatorcontrib>Patrucco, Enrico</creatorcontrib><creatorcontrib>Scardaci, Rossella</creatorcontrib><creatorcontrib>Savinelli, Ilenia</creatorcontrib><creatorcontrib>Wang, Haiyun</creatorcontrib><creatorcontrib>Qiao, Keying</creatorcontrib><creatorcontrib>Carrà, Giovanna</creatorcontrib><creatorcontrib>Nokin, Marie-Julie</creatorcontrib><creatorcontrib>Zhou, Zhiwei</creatorcontrib><creatorcontrib>Westover, Kenneth D</creatorcontrib><creatorcontrib>Santamaria, David</creatorcontrib><creatorcontrib>Porporato, Paolo E</creatorcontrib><creatorcontrib>Ambrogio, Chiara</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Molecular oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kramer-Drauberg, Maximilian</au><au>Petrini, Ettore</au><au>Mira, Alessia</au><au>Patrucco, Enrico</au><au>Scardaci, Rossella</au><au>Savinelli, Ilenia</au><au>Wang, Haiyun</au><au>Qiao, Keying</au><au>Carrà, Giovanna</au><au>Nokin, Marie-Julie</au><au>Zhou, Zhiwei</au><au>Westover, Kenneth D</au><au>Santamaria, David</au><au>Porporato, Paolo E</au><au>Ambrogio, Chiara</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oncogenic mutant KRAS inhibition through oxidation at cysteine 118</atitle><jtitle>Molecular oncology</jtitle><addtitle>Mol Oncol</addtitle><date>2025-01-21</date><risdate>2025</risdate><issn>1574-7891</issn><issn>1878-0261</issn><eissn>1878-0261</eissn><abstract>Specific reactive oxygen species activate the GTPase Kirsten rat sarcoma virus (KRAS) by reacting with cysteine 118 (C118), leading to an electron transfer between C118 and nucleoside guanosine diphosphate (GDP), which causes the release of GDP. Here, we have mimicked permanent oxidation of human KRAS at C118 by replacing C118 with aspartic acid (C118D) in KRAS to show that oncogenic mutant KRAS is selectively inhibited via oxidation at C118, both in vitro and in vivo. Moreover, the combined treatment of hydrogen-peroxide-producing pro-oxidant paraquat and nitric-oxide-producing inhibitor N(ω)-nitro-l-arginine methyl ester selectively inhibits human mutant KRAS activity by inducing oxidization at C118. Our study shows for the first time the vulnerability of human mutant KRAS to oxidation, thereby paving the way to explore oxidation-based anti-KRAS treatments in humans.</abstract><cop>United States</cop><pmid>39838816</pmid><doi>10.1002/1878-0261.13798</doi><orcidid>https://orcid.org/0000-0001-8519-1552</orcidid><orcidid>https://orcid.org/0000-0003-4122-701X</orcidid><orcidid>https://orcid.org/0000-0002-6263-6800</orcidid><oa>free_for_read</oa></addata></record>
fulltext fulltext
identifier ISSN: 1574-7891
ispartof Molecular oncology, 2025-01
issn 1574-7891
1878-0261
1878-0261
language eng
recordid cdi_proquest_miscellaneous_3158101018
source Wiley Online Library; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Wiley Open Access; PubMed Central; Directory of Open Access Journals
title Oncogenic mutant KRAS inhibition through oxidation at cysteine 118
url https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-05T20%3A58%3A40IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Oncogenic%20mutant%20KRAS%20inhibition%20through%20oxidation%20at%20cysteine%20118&rft.jtitle=Molecular%20oncology&rft.au=Kramer-Drauberg,%20Maximilian&rft.date=2025-01-21&rft.issn=1574-7891&rft.eissn=1878-0261&rft_id=info:doi/10.1002/1878-0261.13798&rft_dat=%3Cproquest_cross%3E3158101018%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3158101018&rft_id=info:pmid/39838816&rfr_iscdi=true