Port, J. et al. (2018) Colorectal tumors require NUAK1 for protection from oxidative stress. Cancer Discovery, 8(5), pp. 632-647. (doi: 10.1158/2159-8290.CD-17-0533) (PMID:29500295) (PMCID:PMC5935231)
|
Text
157305.pdf - Accepted Version 2MB |
Abstract
Exploiting oxidative stress has recently emerged as a plausible strategy for treatment of human Cancer and anti-oxidant defences are implicated in resistance to chemo- and radiotherapy. Targeted suppression of anti-oxidant defences could thus broadly improve therapeutic outcomes. Here we identify the AMPK-related kinase NUAK1 as a key component of the anti-oxidant stress response pathway and reveal a specific requirement for this role of NUAK1 in colorectal cancer. We show that NUAK1 is activated by oxidative stress and that this activation is required to facilitate nuclear import of the anti-oxidant master regulator NRF2: Activation of NUAK1 coordinates PP1β inhibition with AKT activation in order to suppress GSK3β-dependent inhibition of NRF2 nuclear import. Deletion of NUAK1 suppresses formation of colorectal tumors, while acute depletion of NUAK1 induces regression of pre-existing autochthonous tumors. Importantly, elevated expression of NUAK1 in human colorectal cancer is associated with more aggressive disease and reduced overall survival.
Item Type: | Articles |
---|---|
Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Monteverde, Tiziana and Gyuraszova, Dr Katarina and Murphy, Professor Daniel and Sumpton, Mr David and Brucoli, Martina and Nixon, Mr Colin and Neilson, Ms Lisa and Lilla, Dr Sergio and Drysdale, Dr Martin and PORT, Jennifer and Tait-Mulder, Dr Jacqueline and Zanivan, Professor Sara and Mezna, Dr Mokdad and McVie, Mr Allan and Raja, Miss Meera and Kalna, Dr Gabriela and Ceteci, Dr Fatih and Kruspig, Dr Bjorn and Sansom, Professor Owen |
Authors: | Port, J., Muthalagu, N., Raja, M., Ceteci, F., Monteverde, T., Kruspig, B., Hedley, A., Kalna, G., Lilla, S., Neilson, L., Brucoli, M., Gyuraszova, K., Tait-Mulder, J., Mezna, M., Svambaryte, S., Bryson, A., Sumpton, D., McVie, A., Nixon, C., Drysdale, M., Esumi, H., Murray, G. I., Sansom, O. J., Zanivan, S. R., and Murphy, D. J. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
Journal Name: | Cancer Discovery |
Publisher: | American Association for Cancer Research |
ISSN: | 2159-8274 |
ISSN (Online): | 2159-8290 |
Published Online: | 02 March 2018 |
Copyright Holders: | Copyright © 2018 American Association for Cancer Research |
First Published: | First published in Cancer Discovery 8(5): 632-647 |
Publisher Policy: | Reproduced in accordance with the publisher copyright policy |
University Staff: Request a correction | Enlighten Editors: Update this record