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; Hiroyasu Esumi; Graeme I. Murray; Owen J. Sansom; Sara Zanivan; Daniel J. Murphy

doi:10.1158/2159-8290.CD-17-0533

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

Applied Medicine

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	633-647
Number of pages	15
Journal	Cancer Discovery
Volume	8
Issue number	5
Early online date	2 Mar 2018
DOIs	https://doi.org/10.1158/2159-8290.CD-17-0533
Publication status	Published - May 2018

Bibliographical 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”.

Keywords

NUAK1
ARK5
NRF2
oxidative stress
colorectal cancer
cancer therapy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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

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

@article{1b9f29b762b84ddba507c2dea56899e3,

title = "Colorectal tumors require NUAK1 for protection from oxidative stress",

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.",

keywords = "NUAK1 , ARK5 , NRF2, oxidative stress, colorectal cancer, cancer therapy",

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”. ",

year = "2018",

month = may,

doi = "10.1158/2159-8290.CD-17-0533",

language = "English",

volume = "8",

pages = "633--647",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "5",

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TY - JOUR

T1 - Colorectal tumors require NUAK1 for protection from oxidative stress

AU - Port, Jennifer L. F.

AU - Muthalagu, Nathiya

AU - Raja, Meera

AU - Ceteci, Fatih

AU - Monteverde, Tiziana

AU - Kruspig, Bjorn

AU - Hedley, Ann

AU - Kalna, Gabriela

AU - Lilla, Sergio

AU - Neilson, Lisa

AU - Brucoli, Martina

AU - Gyuraszova, Katarina

AU - Tait-Mulder, Jacqueline

AU - Mezna, Mokdad

AU - Svambaryte, Silvija

AU - Bryson, Amy

AU - Sumpton, David

AU - McVie, Allan

AU - Nixon, Colin

AU - Drysdale, Martin

AU - Esumi, Hiroyasu

AU - Murray, Graeme I.

AU - Sansom, Owen J.

AU - Zanivan, Sara

AU - Murphy, Daniel J.

N1 - 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”.

PY - 2018/5

Y1 - 2018/5

N2 - 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.

AB - 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.

KW - NUAK1

KW - ARK5

KW - NRF2

KW - oxidative stress

KW - colorectal cancer

KW - cancer therapy

U2 - 10.1158/2159-8290.CD-17-0533

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

M3 - Article

SN - 2159-8274

VL - 8

SP - 633

EP - 647

JO - Cancer Discovery

JF - Cancer Discovery

IS - 5

ER -

Colorectal tumors require NUAK1 for protection from oxidative stress

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

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Cite this