American Association for Cancer Research
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21598290cd170533-sup-183301_2_supp_4576710_p4cq1p.xlsx (32.5 kB)

Supplementary Table 3 from Colorectal Tumors Require NUAK1 for Protection from Oxidative Stress

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posted on 2023-04-03, 21:45 authored by Jennifer Port, Nathiya Muthalagu, Meera Raja, Fatih Ceteci, Tiziana Monteverde, Björn Kruspig, Ann Hedley, Gabriela Kalna, Sergio Lilla, Lisa Neilson, Martina Brucoli, Katarina Gyuraszova, Jacqueline Tait-Mulder, Mokdad Mezna, Silvija Svambaryte, Amy Bryson, David Sumpton, Allan McVie, Colin Nixon, Martin Drysdale, Hiroyasu Esumi, Graeme I. Murray, Owen J. Sansom, Sara R. Zanivan, Daniel J. Murphy

Excel spreadsheet of NUAK1 inhibitor induced phospho-peptide alterations

Funding

CRUK

European Commission Marie

AICR

EC Marie Curie

British Lung Foundation

Cancer Research UK

European Research Council

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ARTICLE ABSTRACT

Exploiting oxidative stress has recently emerged as a plausible strategy for treatment of human cancer, and antioxidant defenses are implicated in resistance to chemotherapy and radiotherapy. Targeted suppression of antioxidant defenses could thus broadly improve therapeutic outcomes. Here, we identify the AMPK-related kinase NUAK1 as a key component of the antioxidant 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 antioxidant 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, whereas acute depletion of NUAK1 induces regression of preexisting autochthonous tumors. Importantly, elevated expression of NUAK1 in human colorectal cancer is associated with more aggressive disease and reduced overall survival.Significance: This work identifies NUAK1 as a key facilitator of the adaptive antioxidant response that is associated with aggressive disease and worse outcome in human colorectal cancer. Our data suggest that transient NUAK1 inhibition may provide a safe and effective means for treatment of human colorectal cancer via disruption of intrinsic antioxidant defenses. Cancer Discov; 8(5); 632–47. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 517