Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between Gill and β catenin through activation of GSK3β

Presences of cancer stem cells (CSCs) in a bulk of cancer cells are responsible for tumor relapse, metastasis and drug resistance in oral cancer. Due to high drug efflux, DNA repair and self-renewable capacity of CSCs, the conventional chemotherapeutic agents are unable to kill the CSCs. CSCs utilizes Hedgehog (HH-GLI), WNT-(3 catenin signalling for its growth and development GSK3 beta negatively regulates both the pathways in CSCs. Here, we have shown that a nano-formulated bioactive small molecule inhibitor Quinacrine (NQC) caused apoptosis in oral cancer stem cells (OCSCs; isolated from different oral cancer cells and oral cancer patient derived primary cells) by down regulating WNT-(3 catenin and HH-GLI components through activation of GSK3 beta. NQC activates GSK3 beta in transcriptional and translational level and reduces beta catenin and GLI1 as well as downstream target gene of both the pathways Cyclin D1, C-Myc. The transcription factor activity of both the pathways was also reduced by NQC treatment. GSK3 beta, beta catenin and GM interacts with each other and NQC disrupts the co-localization and interaction between beta catenin and GLI1 in OCSCs in a dose dependent manner through activation of GSK3 beta. Thus, data suggest NQC caused OCSCs death by disrupting the crosstalk between beta catenin and GLI1 by activation of GSK3 beta. (C) 2017 Elsevier Inc. All rights reserved.