Abstract
Advanced breast cancer (eg. stage IV) is resistant to chemotherapy. In this work, we identified potentially druggable targets that are critically involved in chemoresistance. We showed that eIF4E is highly phosphorylated at serine 209 in breast cancer patients in response to chemotherapy, which significantly correlated with poorer clinical responses and outcomes. Depletion of eIF4E enhanced the anti-proliferative and pro-apoptotic effects of chemotherapeutic drugs in breast cancer cells. Chemotherapy activated the Wnt/β-catenin signaling in an eIF4E-dependent manner. However, MNK inhibitors prevented chemotherapeutic drug-induced eIF4E phosphorylation and β-catenin activation, which enhanced the breast cancer cell response to chemotherapy in vitro and in vivo. These findings indicate MNK-eIF4E-β-catenin is an activator of the breast cancer cell response to chemotherapy and highlights the therapeutic value of inhibiting MNK to overcome chemoresistance in breast cancer.
Highlights
Breast cancer represents a major health problem and is one of leading causes of cancer related mortality in women [1]
Eukaryotic translation initiation factor 4E is essential for cap-dependent mRNA translation and represents a key regulatory node in the control of protein expression [3, 4]. eIF4E overexpression/ activation correlates with poor clinical outcome in human cancers as it promotes the translation of carcinogenesis associated mRNAs [5, 6]
We found that phosphorylation levels of eIF4E at Ser209 were significantly increased in all patient samples received chemotherapy, such as doxorubicin, cyclophosphamide or fluorouracil (Figure 1A)
Summary
Breast cancer represents a major health problem and is one of leading causes of cancer related mortality in women [1]. EIF4E overexpression/ activation correlates with poor clinical outcome in human cancers as it promotes the translation of carcinogenesis associated mRNAs [5, 6]. MAPK-interacting kinase (MNK) can directly regulate eIF4E phosphorylation in response to a variety of signals affecting tumor cell growth [7, 8]. MNK kinases are required for eIF4E phosphorylation at Ser209 in tumor cells, but not normal cells [9]. EIF4E knockdown reportedly decreases the breast cancer cell proliferation, and inhibition of MNK kinase activity by cercosporamide or CGP57380 effectively targets lung, prostate and breast cancer cells [7, 10,11,12]. The role of eIF4E phosphorylation in breast cancer resistance to chemotherapy is unknown
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