کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5558463 | 1561132 | 2017 | 12 صفحه PDF | دانلود رایگان |
- Nano-formulated quinacrine (NQC) activates GSK3β in oral cancer stem cells (OCSCs) in vitro and ex vivo.
- NQC induces apoptosis in OCSCs by inhibiting WNT-β catenin and HH-GLI cascade in vitro and ex vivo.
- NQC disrupts the interaction and co-localization between GLI1 and β catenin.
- NQC-mediated disruption of the crosstalk between GLI1 and β catenin is GSK3β dependent.
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-β catenin signalling for its growth and development. GSK3β 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-β catenin and HH-GLI components through activation of GSK3β. NQC activates GSK3β in transcriptional and translational level and reduces β 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. GSK3β, β catenin and GLI1 interacts with each other and NQC disrupts the co-localization and interaction between β catenin and GLI1 in OCSCs in a dose dependent manner through activation of GSK3β. Thus, data suggest NQC caused OCSCs death by disrupting the crosstalk between β catenin and GLI1 by activation of GSK3β.
Schematic representation of inhibition of HH-GLI and WNT-β catenin cross talk by NQC through GSK3β. Diagram showing HH-GLI and WNT-β catenin pathway, where GLI1 and β catenin and other components were co-localized in a complex and co-ordinately regulate the downstream target genes. NQC activates GSK3β, which further phosphorylates and activates the β catenin and GLI1. Activated β catenin and GLI1 were degraded by proteosomal degradation pathway and unable to translocate into nucleus as a result growth of cells inhibited.177
Journal: Toxicology and Applied Pharmacology - Volume 330, 1 September 2017, Pages 53-64