The role of MNK proteins and eIF4E phosphorylation in breast cancer cell proliferation and survival.
eIF4E is over-expressed in many tumours, including a high proportion of breast cancers. eIF4E is an oncogene, and signalling pathways which promote eIF4E activity represent potential targets for therapeutic intervention in cancer. MNKs phosphorylate eIF4E on serine 209, a modification that can be required for eIF4E-dependent cell transformation. There is therefore a clear requirement to determine the role of MNKs in the proliferation and survival of cells from the major human tumours, such as breast cancer. Phosphorylated eIF4E protein was readily detectable in some breast tumour samples, but was below the limits of detection in others. Of 6 breast cancer cell lines representing the major sub-types of breast cancer, phosphorylated eIF4E was readily detectable in 5 of them, with MCF-7 cells displaying markedly lower levels. Long term colony forming assays demonstrated that all the five lines with high levels of phosphorylated eIF4E were highly sensitive to a MNK inhibitor. In short term assays, a range of responses was revealed. MCF-7 cells were insensitive in both assays. The anti-proliferative effects of the MNK inhibitor in breast cancer cells are primarily cytostatic, rather than cytotoxic, and are potentially due to the inhibition of cyclin D1 synthesis. Our data provide evidence that the sensitivity of breast cancer cells to MNK inhibition may correlate with baseline levels of eIF4E phosphorylation, and suggest that a proportion of breast cancers could be sensitive to inhibiting MNK kinase activity, and that the presence of phosphorylated eIF4E could provide a biomarker for the identification of responsive tumours.
Wheater
Matthew J
MJ
Southampton Cancer Research UK Centre, University of Southampton School of Medicine, MP824 Southampton General Hospital, UK.
Johnson
Peter Wm
PW
Blaydes
Jeremy P
JP
D000814:Aniline Compounds / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D019938:Cyclin D1 / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism*; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology
D000814:Aniline Compounds; C466997:CGP 57380; D039561:Eukaryotic Initiation Factor-4E; D047908:Intracellular Signaling Peptides and Proteins; D011687:Purines; D019938:Cyclin D1; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases