Colorectal tumors require NUAK1 for protection from oxidative stress

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)

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)

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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:Tait-Mulder, Dr Jacqueline and Zanivan, Dr Sara Rossana and Mezna, Dr Mokdad and Monteverde, Tiziana and Gyuraszova, Dr Katarina and Murphy, Dr Daniel and Sumpton, Mr David and McVie, Mr Allan and Raja, Miss Meera and Brucoli, Martina and Nixon, Mr Colin and Neilson, Ms Lisa and Lilla, Dr Sergio and Drysdale, Dr Martin and Kalna, Dr Gabriela and PORT, Jennifer 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 > Institute 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

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
632881SERPLUC: Suppression of Enzymes Required for Progression of Lung CancerDaniel MurphyEuropean Commission (EC)618448RI CANCER SCIENCES
717931NuSiCCDaniel MurphyEuropean Commission (EC)705190RI CANCER SCIENCES
631971A versatile spatio-temporally inducible genetically engineered mouse model of mesotheliomaDaniel MurphyBritish Lung Foundation (BLF)APHD13-5RI CANCER SCIENCES