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 Drysdale & 5 others Hiroyasu 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

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Oxidants
Colorectal Neoplasms
Oxidative Stress
Cell Nucleus Active Transport
Neoplasms
Radiotherapy
Drug Therapy
Survival
Therapeutics

Keywords

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

Cite this

Port, J. L. F., Muthalagu, N., Raja, M., Ceteci, F., Monteverde, T., Kruspig, B., ... 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

Colorectal tumors require NUAK1 for protection from oxidative stress. / Port, Jennifer L. F.; Muthalagu, Nathiya; Raja, Meera; Ceteci, Fatih; Monteverde, Tiziana; Kruspig, Bjorn; Hedley, Ann; Kalna, Gabriela; Lilla, Sergio; Neilson, Lisa; Brucoli, Martina; Gyuraszova, Katarina; Tait-Mulder, Jacqueline; Mezna, Mokdad; Svambaryte, Silvija; Bryson, Amy; Sumpton, David; McVie, Allan; Nixon, Colin; Drysdale, Martin; Esumi, Hiroyasu; Murray, Graeme I.; Sansom, Owen J.; Zanivan, Sara; Murphy, Daniel J.

In: Cancer Discovery, Vol. 8, No. 5, 05.2018, p. 633-647.

Research output: Contribution to journalArticle

Port, JLF, 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, GI, Sansom, OJ, Zanivan, S & Murphy, DJ 2018, 'Colorectal tumors require NUAK1 for protection from oxidative stress', Cancer Discovery, vol. 8, no. 5, pp. 633-647. https://doi.org/10.1158/2159-8290.CD-17-0533
Port JLF, Muthalagu N, Raja M, Ceteci F, Monteverde T, Kruspig B et al. Colorectal tumors require NUAK1 for protection from oxidative stress. Cancer Discovery. 2018 May;8(5):633-647. https://doi.org/10.1158/2159-8290.CD-17-0533
Port, Jennifer L. F. ; Muthalagu, Nathiya ; Raja, Meera ; Ceteci, Fatih ; Monteverde, Tiziana ; Kruspig, Bjorn ; Hedley, Ann ; Kalna, Gabriela ; Lilla, Sergio ; Neilson, Lisa ; Brucoli, Martina ; Gyuraszova, Katarina ; Tait-Mulder, Jacqueline ; Mezna, Mokdad ; Svambaryte, Silvija ; Bryson, Amy ; Sumpton, David ; McVie, Allan ; Nixon, Colin ; Drysdale, Martin ; Esumi, Hiroyasu ; Murray, Graeme I. ; Sansom, Owen J. ; Zanivan, Sara ; Murphy, Daniel J. / Colorectal tumors require NUAK1 for protection from oxidative stress. In: Cancer Discovery. 2018 ; Vol. 8, No. 5. pp. 633-647.
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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.",
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author = "Port, {Jennifer L. F.} and Nathiya Muthalagu and Meera Raja and Fatih Ceteci and Tiziana Monteverde and Bjorn Kruspig and Ann Hedley and Gabriela Kalna and Sergio Lilla and Lisa Neilson and Martina Brucoli and Katarina Gyuraszova and Jacqueline Tait-Mulder and Mokdad Mezna and Silvija Svambaryte and Amy Bryson and David Sumpton and Allan McVie and Colin Nixon and Martin Drysdale and Hiroyasu Esumi and Murray, {Graeme I.} and Sansom, {Owen J.} and Sara Zanivan and Murphy, {Daniel J.}",
note = "The authors wish to thank the staff of the CRUK Beatson Institute Biological Services Unit for animal husbandry and assistance with in vivo experiments; the staff of the CRUK BI Histology core facility and William Clark of the NGS core facility; David McGarry, Rene Jackstadt, Jiska Van der Reest, Justin Bower and Heather McKinnon for many helpful discussions, and countless colleagues at the CRUK BI and Glasgow Institute of Cancer Sciences for support; Prem Premsrirut & Mirimus Inc. for design and generation of dox-inducible Nuak1 shRNA expressing mice Nathanael Gray for initial provision of NUAK1 inhibitors. Funding was provided by the University of Glasgow and the CRUK Beaton Institute. J.P. was supported by European Commission Marie Curie actions C.I.G. 618448 “SERPLUC” to D.J.M.; N.M. was supported through Worldwide Cancer (formerly AICR) grant 15-0279 to O.J.S. & D.J.M.; B.K. was funded through EC Marie Curie actions mobility award 705190 “NuSiCC”; T.M. was funded through British Lung Foundation grant APHD13-5. The laboratories of S.R.Z. (A12935), O.J.S. (A21139) and M.D. (A17096) are funded by Cancer Research UK. O.J.S. was additionally supported by European Research Council grant 311301 “ColoCan”.",
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AU - Port, Jennifer L. F.

AU - Muthalagu, Nathiya

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AU - Ceteci, Fatih

AU - Monteverde, Tiziana

AU - Kruspig, Bjorn

AU - Hedley, Ann

AU - Kalna, Gabriela

AU - Lilla, Sergio

AU - Neilson, Lisa

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KW - colorectal cancer

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DO - 10.1158/2159-8290.CD-17-0533

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VL - 8

SP - 633

EP - 647

JO - Cancer Discovery

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