Targeting the eIF4E/β-catenin axis sensitizes cervical carcinoma squamous cells to chemotherapy.

Chemotherapy has improved the clinical outcomes of cervical cancer patients. However, patients develop chemoresistance, whose underlying mechanisms are not well understood. In this study, we investigated the phosphorylation levels of eukaryotic translation initiation factor 4E (eIF4E) in cervical cancer cells subjected to chemotherapy. Results showed that chemotherapeutic drugs significantly increased eIF4E phosphorylation at S209 in HeLa and SiHa cells. Upregulation of phosphorylated eIF4E (p-eIF4E) levels has also been shown in cisplatin-resistant HeLa cells and has been observed to be a common response of cervical cancer patients undergoing chemotherapy. We further showed that chemotherapeutic drugs increase β-catenin activity and mRNA levels of Wnt/β-catenin target genes in cervical cancer cells but not in eIF4E-depleted cells, suggesting that chemotherapeutic drugs activate Wnt/β-catenin signaling in an eIF4E-dependent manner. Inhibiting eIF4E via siRNA knockdown or Wnt/β-catenin using the Wnt inhibitor pyrvinium effectively enhanced the anti-proliferative and pro-apoptotic effects of cisplatin in cervical cancer cells both in vitro and in vivo. Our findings demonstrate that eIF4E/β-catenin signaling plays a positive regulatory role in the resistance of cervical cancer cell to chemotherapy and thus highlight the therapeutic value of eIF4E or β-catenin inhibition in overcoming chemoresistance.