Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/149025
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dc.contributor.authorYurugi, Hajimeen_US
dc.contributor.authorZhuang, Yinyinen_US
dc.contributor.authorSiddiqui, Farid A.en_US
dc.contributor.authorLiang, Hongen_US
dc.contributor.authorRosigkeit, Sebastianen_US
dc.contributor.authorZeng, Yongpengen_US
dc.contributor.authorAbou-Hamdan, Husseinen_US
dc.contributor.authorBockamp, Ernestoen_US
dc.contributor.authorZhou, Yongen_US
dc.contributor.authorAbankwa, Danielen_US
dc.contributor.authorZhao, Wentingen_US
dc.contributor.authorDésaubry, Laurenten_US
dc.contributor.authorRajalingam, Krishnarajen_US
dc.date.accessioned2021-06-08T14:30:59Z-
dc.date.available2021-06-08T14:30:59Z-
dc.date.issued2020-
dc.identifier.citationYurugi, H., Zhuang, Y., Siddiqui, F. A., Liang, H., Rosigkeit, S., Zeng, Y., Abou-Hamdan, H., Bockamp, E., Zhou, Y., Abankwa, D., Zhao, W., Désaubry, L. & Rajalingam, K. (2020). A subset of flavaglines inhibits KRAS nanoclustering and activation. Journal of Cell Science, 133(12). https://dx.doi.org/10.1242/jcs.244111en_US
dc.identifier.issn0021-9533en_US
dc.identifier.other0000-0002-4175-9633-
dc.identifier.urihttps://hdl.handle.net/10356/149025-
dc.description.abstractThe RAS oncogenes are frequently mutated in human cancers and among the three isoforms (KRAS, HRAS and NRAS), KRAS is the most frequently mutated oncogene. Here, we demonstrate that a subset of flavaglines, a class of natural anti-tumour drugs and chemical ligands of prohibitins, inhibit RAS GTP loading and oncogene activation in cells at nanomolar concentrations. Treatment with rocaglamide, the first discovered flavagline, inhibited the nanoclustering of KRAS, but not HRAS and NRAS, at specific phospholipid-enriched plasma membrane domains. We further demonstrate that plasma membrane-associated prohibitins directly interact with KRAS, phosphatidylserine and phosphatidic acid, and these interactions are disrupted by rocaglamide but not by the structurally related flavagline FL1. Depletion of prohibitin-1 phenocopied the rocaglamide-mediated effects on KRAS activation and stability. We also demonstrate that flavaglines inhibit the oncogenic growth of KRAS-mutated cells and that treatment with rocaglamide reduces non-small-cell lung carcinoma (NSCLC) tumour nodules in autochthonous KRAS-driven mouse models without severe side effects. Our data suggest that it will be promising to further develop flavagline derivatives as specific KRAS inhibitors for clinical applications.en_US
dc.description.sponsorshipNanyang Technological Universityen_US
dc.language.isoenen_US
dc.relationM4082114en_US
dc.relationM4082292en_US
dc.relation.ispartofJournal of Cell Scienceen_US
dc.rights© 2020 The Author(s). All rights reserved. This paper was published by The Company of Biologists Ltd in Journal of Cell Science and is made available with permission of The Author(s).en_US
dc.subjectEngineering::Bioengineeringen_US
dc.titleA subset of flavaglines inhibits KRAS nanoclustering and activationen_US
dc.typeJournal Articleen
dc.contributor.schoolSchool of Chemical and Biomedical Engineeringen_US
dc.identifier.doi10.1242/jcs.244111-
dc.description.versionPublished versionen_US
dc.identifier.pmid32501281-
dc.identifier.scopus2-s2.0-85088206576-
dc.identifier.issue12en_US
dc.identifier.volume133en_US
dc.identifier.spageJCS244111en_US
dc.subject.keywordsKRASen_US
dc.subject.keywordsPhospholipiden_US
dc.description.acknowledgementPart of this work is supported through a Deutsche Forschungsgemeinschaft (DFG) grant RA1739/8-1 to K.R. and CRC1292 (TP05). K.R. is a Heisenberg professor of the DFG and a GFK (Gutenberg Forschungskollegs) fellow. Financial support to W.Z. was provided by a NTU (Nanyang Technological University) Start-Up-Grant (M4082114) NTU-NNI Joint Grant (M4082292).en_US
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