Targeting of MNK/eIF4E overcomes chemoresistance in cervical cancer

Abstract

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.

MNK Proteins as Therapeutic Targets in Leukemia

“… 83 Similarly, in cervical cancer, combination of cercosporamide with chemotherapy drugs, doxorubicin and cisplatin, had increased efficacy in proliferation reduction and apoptosis induction; cercosporamide inhibited chemo-resistant cells and phosphorylation of eIF4E at serine 209 was shown to be induced with chemotherapy treatment. 84 In AML, MNK inhibitors have similarly been shown to sensitize cells to the chemotherapy drug cytarabine. We previously reported the activation of the MNK pathway by cytarabine in AML cells and that the combination of the MNK inhibitor, CGP57380, or MNK knockdown with cytarabine enhances the inhibition of leukemic progenitor colony formation.…”