A10
The role of eIF4E phosphorylation by MNKs in the proliferation and survival of breast cancer cells
Matthew Wheater, Edward Alveyn, Peter W.M. Johnson, Jeremy Blaydes
CRUK Clinical Centre, University of Southampton, UK
Background
Eukaryotic initiation factor 4E (eIF4E) is an oncogene over-expressed in breast cancers. It is associated with a worse risk of recurrence in early stage disease. It is responsible for regulation of synthesis of proteins involved in progression to the malignant phenotype, including Cyclin D1, VEGF and MDM2. The oncogenic activity of eIF4E has been shown to be dependent on phosphorylation at serine 209 by the mitogen-activating protein kinase signal-integrating kinases (MNKs). We have investigated the role of eIF4E phosphorylation in the proliferation and survival of a panel of breast cancer cell lines.
Method
We analysed a panel of breast cancer cell lines for protein expression of MNKs, eIF4E, its phosphorylated form (peIF4E), and protein products of eIF4E regulated mRNAs. We used an inhibitor of the MNKs (CGP57380) to target eIF4E phosphorylation and measured its effect on cancer cell proliferation and survival using a variety of techniques. We assessed the effects of MNK inhibition on eIF4E phosphorylation and on mitotic and apoptotic events.
Results
Cell lines can be categorised into 3 groups based on their level of expression of peIF4E and their response to CGP57380. Those lines both expressing high levels of peIF4E and responding to MNK inhibition include HER2 over-expressing and a line with a K-ras activating mutation. Other lines failed to respond to MNK inhibition. The K-ras mutant cell line showed fewer mitoses when treated with CGP57380 compared with control with no change in apoptotic events, whereas a HER2 over-expressing line showed both reduced mitoses and increased apoptosis.
Conclusion
Inhibition of MNKs by CGP57380 causes inhibition of proliferation in HER2 over-expressing and a K-ras mutant breast cancer cell line. This is consistent with interruption of signalling through the MAPK pathway. The balance between apoptotic and mitotic response to MNK inhibition shows cell line dependency.
