Colorectal tumors require NUAK1 for protection from oxidative stress

Jennifer L. F. Port, Nathiya Muthalagu, Meera Raja, Fatih Ceteci, Tiziana Monteverde, Bjorn 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 DrysdaleHiroyasu Esumi, Graeme I. Murray, Owen J. Sansom, Sara Zanivan, Daniel J. Murphy

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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.
Original languageEnglish
Pages (from-to)633-647
Number of pages15
JournalCancer Discovery
Volume8
Issue number5
Early online date2 Mar 2018
DOIs
Publication statusPublished - May 2018

Keywords

  • NUAK1
  • ARK5
  • NRF2
  • oxidative stress
  • colorectal cancer
  • cancer therapy

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  • Cite this

    Port, J. L. F., 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., ... Murphy, D. J. (2018). Colorectal tumors require NUAK1 for protection from oxidative stress. Cancer Discovery, 8(5), 633-647. https://doi.org/10.1158/2159-8290.CD-17-0533