A subset of flavaglines inhibits KRAS nanoclustering and activation

The 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 loa...

Full description

Saved in:
Bibliographic Details
Main Authors: Yurugi, Hajime, Zhuang, Yinyin, Siddiqui, Farid A., Liang, Hong, Rosigkeit, Sebastian, Zeng, Yongpeng, Abou-Hamdan, Hussein, Bockamp, Ernesto, Zhou, Yong, Abankwa, Daniel, Zhao, Wenting, Désaubry, Laurent, Rajalingam, Krishnaraj
Other Authors: School of Chemical and Biomedical Engineering
Format: Article
Language:English
Published: 2021
Subjects:
Online Access:https://hdl.handle.net/10356/149025
Tags: Add Tag
No Tags, Be the first to tag this record!
Institution: Nanyang Technological University
Language: English
id sg-ntu-dr.10356-149025
record_format dspace
spelling sg-ntu-dr.10356-1490252023-12-29T06:51:09Z A subset of flavaglines inhibits KRAS nanoclustering and activation Yurugi, Hajime Zhuang, Yinyin Siddiqui, Farid A. Liang, Hong Rosigkeit, Sebastian Zeng, Yongpeng Abou-Hamdan, Hussein Bockamp, Ernesto Zhou, Yong Abankwa, Daniel Zhao, Wenting Désaubry, Laurent Rajalingam, Krishnaraj School of Chemical and Biomedical Engineering Engineering::Bioengineering KRAS Phospholipid The 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. Nanyang Technological University Published version Part 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). 2021-06-08T14:30:59Z 2021-06-08T14:30:59Z 2020 Journal Article Yurugi, 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.244111 0021-9533 0000-0002-4175-9633 https://hdl.handle.net/10356/149025 10.1242/jcs.244111 32501281 2-s2.0-85088206576 12 133 JCS244111 en M4082114 M4082292 Journal of Cell Science © 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). application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Engineering::Bioengineering
KRAS
Phospholipid
spellingShingle Engineering::Bioengineering
KRAS
Phospholipid
Yurugi, Hajime
Zhuang, Yinyin
Siddiqui, Farid A.
Liang, Hong
Rosigkeit, Sebastian
Zeng, Yongpeng
Abou-Hamdan, Hussein
Bockamp, Ernesto
Zhou, Yong
Abankwa, Daniel
Zhao, Wenting
Désaubry, Laurent
Rajalingam, Krishnaraj
A subset of flavaglines inhibits KRAS nanoclustering and activation
description The 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.
author2 School of Chemical and Biomedical Engineering
author_facet School of Chemical and Biomedical Engineering
Yurugi, Hajime
Zhuang, Yinyin
Siddiqui, Farid A.
Liang, Hong
Rosigkeit, Sebastian
Zeng, Yongpeng
Abou-Hamdan, Hussein
Bockamp, Ernesto
Zhou, Yong
Abankwa, Daniel
Zhao, Wenting
Désaubry, Laurent
Rajalingam, Krishnaraj
format Article
author Yurugi, Hajime
Zhuang, Yinyin
Siddiqui, Farid A.
Liang, Hong
Rosigkeit, Sebastian
Zeng, Yongpeng
Abou-Hamdan, Hussein
Bockamp, Ernesto
Zhou, Yong
Abankwa, Daniel
Zhao, Wenting
Désaubry, Laurent
Rajalingam, Krishnaraj
author_sort Yurugi, Hajime
title A subset of flavaglines inhibits KRAS nanoclustering and activation
title_short A subset of flavaglines inhibits KRAS nanoclustering and activation
title_full A subset of flavaglines inhibits KRAS nanoclustering and activation
title_fullStr A subset of flavaglines inhibits KRAS nanoclustering and activation
title_full_unstemmed A subset of flavaglines inhibits KRAS nanoclustering and activation
title_sort subset of flavaglines inhibits kras nanoclustering and activation
publishDate 2021
url https://hdl.handle.net/10356/149025
_version_ 1787136710762561536