Targeting of MNK/eIF4E Overcomes Chemoresistance in Cervical Cancer

OBJECTIVES:Eukaryotic translation initiation factor 4E (eIF4E) is activated in cancers in response to stress. This is regulated by MAP kinase interacting serine/threonine kinase (MNK) in cancerous but not normal cells. Chemoresistance causes treatment failure in advanced cervical cancer. In this study, we addressed chemotherapy effects on eIF4E for cervical cancer and reversal effects by MNK inhibitor cercosporamide for chemo-resistance mitigation.METHODS:Cell assays and mouse tumour models were used to determine the efficacy of cercosporamide. Western blotting was applied to understand the affected cell signaling after cercosporamide treatment.KEY FINDINGS:Cercosporamide spared normal cervical epithelial cells. On cervical cancer cell lines, it showed inhibition of cell growth and migration, and induced apoptosis. Cercosporamide was effective on chemoresistant cancer cells and augmented the efficiency of doxorubicin and cisplatin both in vitro and in vivo. Cercosporamide suppressed eIF4E signaling. Of note, chemotherapy increased p-eIF4E. Cercosporamide abolished chemotherapy-induced eIF4E activation. The higher level of p-eIF4E in cancer cells compared with normal cervical epithelial cells explains the preferential toxicity of cercosporamide.CONCLUSIONS:This work demonstrates the ability of cercosporamide to overcome chemoresistance and highlight preferential inhibition of eIF4E via MNK inhibition in cervical cancer.