Oncogenic MNK Signalling Regulates the Metastasis Suppressor NDRG1

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 May 26

PMID 28545025

Citations 10

Authors

Shuye Tian

Xuemin Wang

Christopher G Proud

Affiliations

Soon will be listed here.

Abstract

The protein N-myc down-regulated gene 1 (NDRG1) represses tumour metastasis. It is phosphorylated at several sites by serum and glucocorticoid-regulated kinase 1 (SGK1). Here we show that NDRG1 is also regulated by the oncogenic MAP kinase-interacting kinase (MNK) pathway, a target for cancer therapy.Inhibiting MNKs increases the expression of NDRG1 protein and mRNA in breast cancer cells. MNK inhibition also decreases the phosphorylation of NDRG1. Phosphorylation of NDRG1 is reduced in cells lacking MNK1, but not MNK2-knockout cells, indicating that NDRG1 phosphorylation is a specific target for MNK1. However, MNK1 cannot directly phosphorylate NDRG1 in vitro, indicating that additional signalling connections are involved. Taken together, our data indicate that MNK signaling regulates NDRG1 at transcriptional and post-translational levels.We show that SGK1 phosphorylates MNK1 at a conserved site, which represses its activity. NDRG1, SGK1 and the MNKs are implicated in cell migration and metastasis. As expected, knocking-down NDRG1 promoted cell migration. However, whereas MNK inhibition impairs these processes irrespective of NDRG1 levels, SGK inhibition only did so in NDRG1-depleted cells. Thus, MNKs and SGK affect migration/invasion through distinct mechanisms.Our data reveal several novel connections between signalling pathways important for tumour biology.

Citing Articles

NDRGs in Breast Cancer: A Review and In Silico Analysis.

Villodre E, Nguyen A, Debeb B Cancers (Basel). 2024; 16(7).

PMID: 38611020 PMC: 11011033. DOI: 10.3390/cancers16071342.

An Aptamer against MNK1 for Non-Small Cell Lung Cancer Treatment.

Carrion-Marchante R, Pinto-Diez C, Klett-Mingo J, Palacios E, Barragan-Usero M, Perez-Morgado M Pharmaceutics. 2023; 15(4).

PMID: 37111758 PMC: 10146192. DOI: 10.3390/pharmaceutics15041273.

NDRG1 in Aggressive Breast Cancer Progression and Brain Metastasis.

Villodre E, Hu X, Eckhardt B, Larson R, Huo L, Yoon E J Natl Cancer Inst. 2021; 114(4):579-591.

PMID: 34893874 PMC: 9002276. DOI: 10.1093/jnci/djab222.

SGK1, autophagy and cancer: an overview.

Ghani M Mol Biol Rep. 2021; 49(1):675-685.

PMID: 34669124 DOI: 10.1007/s11033-021-06836-6.

SGK1 in Human Cancer: Emerging Roles and Mechanisms.

Sang Y, Kong P, Zhang S, Zhang L, Cao Y, Duan X Front Oncol. 2021; 10:608722.

PMID: 33542904 PMC: 7851074. DOI: 10.3389/fonc.2020.608722.

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