Combined GSK-3β and MEK inhibitors modulate the stemness and radiotherapy sensitivity of cervical cancer stem cells through the Wnt signaling pathway

Abstract

Cancer stem cells (CSCs) are the basis of cancer and lead to the recurrence and metastasis of cervical cancer. The aim of this study was to investigate the effects of antineoplastic agents on the stemness and radiotherapy sensitivity of cervical CSCs. Side population (SP) and non-side population (NSP) cells from the SiHa cervical cancer cell line were separated using flow cytometry. The cell spheroidization, proliferation, and subcutaneous tumor formation abilities of SP cells were stronger than those of NSP cells, and cervical CSC marker expressions increased in SP cells. The proliferation, anti-apoptosis and migration of SP cells under ionizing radiation were higher than those of SiHa cells. GSK-3β and/or MEK inhibitors can increase the proliferation, migration and anti-apoptosis of SP cells, and CSC marker expressions. The Wnt pathway inhibitor decreased CSC stemness maintenance by combination of GSK-3β and MEK inhibitors. Injection of GSK-3β and MEK inhibitors under ionizing radiation promoted tumor growth and activated downstream factor expressions in the Wnt signaling pathway in vivo. This study demonstrated that combining GSK-3β and MEK inhibitors can activate Wnt signaling pathway in cervical CSCs, thereby affecting their stemness maintenance and radiotherapy sensitivity.