Synergistic effects of inhibiting the MNK-eIF4E and PI3K/AKT/ mTOR pathways on cell migration in MDA-MB-231 cells

Ella Lineham; Graham J. Tizzard; Simon J. Coles; John Spencer; Simon J. Morley

doi:10.18632/oncotarget.24354

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Research Papers:

Synergistic effects of inhibiting the MNK-eIF4E and PI3K/AKT/ mTOR pathways on cell migration in MDA-MB-231 cells

Ella Lineham _, Graham J. Tizzard, Simon J. Coles, John Spencer and Simon J. Morley

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Oncotarget. 2018; 9:14148-14159. https://doi.org/10.18632/oncotarget.24354

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Abstract

Ella Lineham1, Graham J. Tizzard2, Simon J. Coles2, John Spencer3 and Simon J. Morley1

1Department of Biochemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, UK

2UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield, Southampton, UK

3Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, UK

Correspondence to:

Simon J. Morley, email: [email protected]

Keywords: cell signaling; migration; kinase; dual inhibitors

Received: December 19, 2017 Accepted: January 25, 2018 Epub: January 31, 2018 Published: March 06, 2018

ABSTRACT

The study of eukaryotic initiation factor 4E (eIF4E) is a key focus in cancer research due to its role in controlling the translation of tumour-associated proteins, that drive an aggressive migratory phenotype. eIF4E is a limiting component of the eIF4F complex which is a critical determinant for the translation of mRNAs. Mitogen-activated protein kinase interacting protein kinases (MNK1/2) phosphorylate eIF4E on Ser209, promoting the expression of oncogenic proteins, whereas mTORC1 phosphorylates and de-activates the eIF4E inhibitor, 4E-BP1, to release translational repression. Here we show that inhibiting these pathways simultaneously effectively slows the rate of cell migration in breast cancer cells. However, a molecular hybridisation approach using novel, cleavable dual MNK1/2 and PI3K/mTOR inhibiting hybrid agents was less effective at slowing cell migration.

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Research Papers:

Synergistic effects of inhibiting the MNK-eIF4E and PI3K/AKT/ mTOR pathways on cell migration in MDA-MB-231 cells

Abstract