Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between GLI1 and beta catenin through activation of GSK3beta.

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-beta catenin signalling for its growth and development. GSK3beta 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-beta catenin and HH-GLI components through activation of GSK3beta. NQC activates GSK3beta 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. GSK3beta, beta catenin and GLI1 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 GSK3beta. Thus, data suggest NQC caused OCSCs death by disrupting the crosstalk between beta catenin and GLI1 by activation of GSK3beta.