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Title: Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between GLI1 and β catenin through activation of GSK3β

Abstract

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 andmore » GLI1 by activation of GSK3β. - Graphical abstract: 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. - Highlights: • 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.« less

Authors:
; ; ; ; ;
Publication Date:
OSTI Identifier:
22722912
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 330; Other Information: Copyright (c) 2017 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; APOPTOSIS; DNA REPAIR; INHIBITION; INTERACTIONS; NEOPLASMS; PLANT GROWTH; STEM CELLS; TRANSCRIPTION FACTORS

Citation Formats

Nayak, Anmada, Siddharth, Sumit, Das, Sarita, Nayak, Deepika, Sethy, Chinmayee, and Kundu, Chanakya Nath, E-mail: cnkundu@kiitbiotech.ac.in. Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between GLI1 and β catenin through activation of GSK3β. United States: N. p., 2017. Web. doi:10.1016/J.TAAP.2017.07.008.
Nayak, Anmada, Siddharth, Sumit, Das, Sarita, Nayak, Deepika, Sethy, Chinmayee, & Kundu, Chanakya Nath, E-mail: cnkundu@kiitbiotech.ac.in. Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between GLI1 and β catenin through activation of GSK3β. United States. doi:10.1016/J.TAAP.2017.07.008.
Nayak, Anmada, Siddharth, Sumit, Das, Sarita, Nayak, Deepika, Sethy, Chinmayee, and Kundu, Chanakya Nath, E-mail: cnkundu@kiitbiotech.ac.in. Fri . "Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between GLI1 and β catenin through activation of GSK3β". United States. doi:10.1016/J.TAAP.2017.07.008.
@article{osti_22722912,
title = {Nanoquinacrine caused apoptosis in oral cancer stem cells by disrupting the interaction between GLI1 and β catenin through activation of GSK3β},
author = {Nayak, Anmada and Siddharth, Sumit and Das, Sarita and Nayak, Deepika and Sethy, Chinmayee and Kundu, Chanakya Nath, E-mail: cnkundu@kiitbiotech.ac.in},
abstractNote = {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. - Graphical abstract: 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. - Highlights: • 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.},
doi = {10.1016/J.TAAP.2017.07.008},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 330,
place = {United States},
year = {2017},
month = {9}
}