Colorectal Tumors Require NUAK1 for Protection from Oxidative Stress
| Autor: | Daniel J. Murphy, Mokdad Mezna, Fatih Ceteci, Lisa J. Neilson, Martin J. Drysdale, Sergio Lilla, Gabriela Kalna, David Sumpton, Nathiya Muthalagu, Allan McVie, Jennifer Port, Katarina Gyuraszova, Ann Hedley, Amy Bryson, Tiziana Monteverde, Graeme I. Murray, Jacqueline Tait-Mulder, Sara Zanivan, Martina Brucoli, Hiroyasu Esumi, Björn Kruspig, Silvija Svambaryte, Meera Raja, Colin Nixon, Owen J. Sansom |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Colorectal cancer NF-E2-Related Factor 2 medicine.medical_treatment NUAK1 Colonic Polyps Gene Expression medicine.disease_cause Models Biological Article 03 medical and health sciences Mice medicine Animals Humans Nucleotide Motifs Protein kinase B Regulation of gene expression Binding Sites Glycogen Synthase Kinase 3 beta Kinase business.industry Cancer medicine.disease Prognosis 3. Good health Radiation therapy Gene Expression Regulation Neoplastic Repressor Proteins Disease Models Animal Oxidative Stress Protein Transport 030104 developmental biology Oncology Cancer research Disease Progression Lymph Nodes business Colorectal Neoplasms Reactive Oxygen Species Protein Kinases Oxidative stress Biomarkers Protein Binding |
| Zdroj: | Cancer Discovery |
| ISSN: | 2159-8274 |
| DOI: | 10.1158/2159-8290.CD-17-0533 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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