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...
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| Format: | Article |
| Language: | English |
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Wiley
2025-02-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13798 |
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| author | Maximilian Kramer‐Drauberg Ettore Petrini Alessia Mira Enrico Patrucco Rossella Scardaci Ilenia Savinelli Haiyun Wang Keying Qiao Giovanna Carrà Marie‐Julie Nokin Zhiwei Zhou Kenneth D. Westover David Santamaria Paolo E. Porporato Chiara Ambrogio |
| author_facet | Maximilian Kramer‐Drauberg Ettore Petrini Alessia Mira Enrico Patrucco Rossella Scardaci Ilenia Savinelli Haiyun Wang Keying Qiao Giovanna Carrà Marie‐Julie Nokin Zhiwei Zhou Kenneth D. Westover David Santamaria Paolo E. Porporato Chiara Ambrogio |
| author_sort | Maximilian Kramer‐Drauberg |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-84af2962b2cd4f30905eaf3ff2e7ea61 |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-84af2962b2cd4f30905eaf3ff2e7ea612025-02-04T17:30:20ZengWileyMolecular Oncology1574-78911878-02612025-02-0119231132810.1002/1878-0261.13798Oncogenic mutant KRAS inhibition through oxidation at cysteine 118Maximilian Kramer‐Drauberg0Ettore Petrini1Alessia Mira2Enrico Patrucco3Rossella Scardaci4Ilenia Savinelli5Haiyun Wang6Keying Qiao7Giovanna Carrà8Marie‐Julie Nokin9Zhiwei Zhou10Kenneth D. Westover11David Santamaria12Paolo E. Porporato13Chiara Ambrogio14Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center University of Torino ItalyDepartment of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center University of Torino ItalyDepartment of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center University of Torino ItalyDepartment of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center University of Torino ItalyDepartment of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center University of Torino ItalyDepartment of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center University of Torino ItalySchool of Life Sciences and Technology Tongji University Shanghai ChinaSchool of Life Sciences and Technology Tongji University Shanghai ChinaDepartment of Clinical and Biological Sciences University of Torino Orbassano ItalyLaboratory of Tumor and Development Biology, GIGA‐Cancer University of Liege BelgiumDepartment of Biochemistry The University of Texas Southwestern Medical Center Dallas TX USADepartment of Biochemistry The University of Texas Southwestern Medical Center Dallas TX USAMolecular Mechanisms of Cancer Program, Centro de Investigación del Cáncer CSIC‐Universidad de Salamanca SpainDepartment of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center University of Torino ItalyDepartment of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center University of Torino ItalySpecific 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.https://doi.org/10.1002/1878-0261.13798cysteine modificationKRAS C118NSCLConcogeneredox regulationROS |
| spellingShingle | Maximilian Kramer‐Drauberg Ettore Petrini Alessia Mira Enrico Patrucco Rossella Scardaci Ilenia Savinelli Haiyun Wang Keying Qiao Giovanna Carrà Marie‐Julie Nokin Zhiwei Zhou Kenneth D. Westover David Santamaria Paolo E. Porporato Chiara Ambrogio Oncogenic mutant KRAS inhibition through oxidation at cysteine 118 Molecular Oncology cysteine modification KRAS C118 NSCLC oncogene redox regulation ROS |
| title | Oncogenic mutant KRAS inhibition through oxidation at cysteine 118 |
| title_full | Oncogenic mutant KRAS inhibition through oxidation at cysteine 118 |
| title_fullStr | Oncogenic mutant KRAS inhibition through oxidation at cysteine 118 |
| title_full_unstemmed | Oncogenic mutant KRAS inhibition through oxidation at cysteine 118 |
| title_short | Oncogenic mutant KRAS inhibition through oxidation at cysteine 118 |
| title_sort | oncogenic mutant kras inhibition through oxidation at cysteine 118 |
| topic | cysteine modification KRAS C118 NSCLC oncogene redox regulation ROS |
| url | https://doi.org/10.1002/1878-0261.13798 |
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