Oncogenic mutant KRAS inhibition through oxidation at cysteine 118
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| Název: | Oncogenic mutant KRAS inhibition through oxidation at cysteine 118 |
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| Autoři: | 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 |
| Přispěvatelé: | Fondazione Umberto Veronesi, ERC - European Research Council, Worldwide Cancer Research, AIRC - Associazione Italiana per la Ricerca sul Cancro, Giovanni Armenise-Harvard Foundation |
| Zdroj: | Mol Oncol Molecular Oncology, Vol 19, Iss 2, Pp 311-328 (2025) |
| Informace o vydavateli: | Wiley, 2025. |
| Rok vydání: | 2025 |
| Témata: | Cancer Research, cysteine modification, KRAS protein, human, Oncologie, NSCLC, Sciences de la santé humaine, Proto-Oncogene Proteins p21(ras)/genetics, redox regulation, Proto-Oncogene Proteins p21(ras), Mice, Cysteine/metabolism, oncogene, Cell Line, Tumor, Genetics, Humans, Animals, Cysteine, Human health sciences, RC254-282, KRAS C118, ROS, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Oncology, Mutation, Molecular Medicine, Proto-Oncogene Proteins p21(ras)/metabolism, Reactive Oxygen Species, Oxidation-Reduction, Research Article |
| Popis: | 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. |
| Druh dokumentu: | Article Other literature type |
| Popis souboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 1878-0261 1574-7891 |
| DOI: | 10.1002/1878-0261.13798 |
| Přístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/39838816 https://doaj.org/article/84af2962b2cd4f30905eaf3ff2e7ea61 https://hdl.handle.net/2268/328671 https://doi.org/10.1002/1878-0261.13798 https://hdl.handle.net/2318/2049950 https://doi.org/10.1002/1878-0261.13798 |
| Rights: | CC BY |
| Přístupové číslo: | edsair.doi.dedup.....11a3c39f286ddf1cda4af4d609bc7eb7 |
| Databáze: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | 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. |
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| ISSN: | 18780261 15747891 |
| DOI: | 10.1002/1878-0261.13798 |