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

// Ella Lineham 1 , Graham J. Tizzard 2 , Simon J. Coles 2 , John Spencer 3 and Simon J. Morley 1 1 Department of Biochemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, UK 2 UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield, Southampton, UK 3 Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, Brighton, UK Correspondence to: Simon J. Morley, email: s.j.morley@sussex.ac.uk 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.