Dataset Information

Colorectal tumors require NUAK1 for protection from oxidative stress

ABSTRACT: NUAK1 is a member of the AMPK family of kinases involved in regulation of cell adhesion, metabolism and stress responses. Our previous analysis revealed a requirement for NUAK1 to sustain viability when MYC is overexpressed. Human colorectal cancer (CRC) shows near uniform overexpression of MYC, suggesting that this cancer may be particularly amenable to NUAK1 inhibition. This work reveals that elevated NUAK1 expression in human CRC correlates with more aggressive disease, lymph node metastasis and reduced overall survival. Deletion of Nuak1 in murine intestines prevented outgrowth of colonic tumors driven by loss of Apc and KRas mutation, while depletion of Nuak1 in pre-existing tumors drove rapid tumor regression. Mechanistically, we show that NUAK1 promotes anti-oxidant gene expression by facilitating nuclear import of NRF2. Deletion or inhibition of NUAK1 renders cells vulnerable to oxidative stress and provision of exogenous anti-oxidants protects cells in culture and colonic tumors in situ from Nuak1 depletion.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Colon

SUBMITTER: Sara Zanivan

LAB HEAD: Sara Zanivan

PROVIDER: PXD008229 | Pride | 2018-02-26

REPOSITORIES: Pride

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			Action	DRS
	20150514_Elite_LiNe_collab_Tiziana_PSTY_HDLH_F1.raw	Raw
	20150514_Elite_LiNe_collab_Tiziana_PSTY_HDLH_F2.raw	Raw
	20150514_Elite_LiNe_collab_Tiziana_PSTY_HDLH_F3.raw	Raw
	20150514_Elite_LiNe_collab_Tiziana_PSTY_HDLH_F4.raw	Raw
	20150514_Elite_LiNe_collab_Tiziana_PSTY_LDHH_F1.raw	Raw

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Colorectal Tumors Require NUAK1 for Protection from Oxidative Stress.

Port Jennifer J Muthalagu Nathiya N Raja Meera M Ceteci Fatih F Monteverde Tiziana T Kruspig Björn B Hedley Ann A Kalna Gabriela G Lilla Sergio S Neilson Lisa L Brucoli Martina M Gyuraszova Katarina K Tait-Mulder Jacqueline J Mezna Mokdad M Svambaryte Silvija S Bryson Amy A Sumpton David D McVie Allan A Nixon Colin C Drysdale Martin M Esumi Hiroyasu H Murray Graeme I GI Sansom Owen J OJ Zanivan Sara R SR Murphy Daniel J DJ

Cancer discovery 20180302 5

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 act ...[more]

PMID: 29500295

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