Please use this identifier to cite or link to this item: https://doi.org/10.3389/fphar.2017.00124
Title: Breast cancer stem-like cells are inhibited by diosgenin, a steroidal saponin, by the attenuation of the Wnt β-catenin signaling via the Wnt antagonist secreted frizzled related protein-4
Authors: Bhuvanalakshmi, G
Basappa, Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore, India
Rangappa, K.S
Dharmarajan, A
Sethi, G 
Kumar, A.P 
Warrier, S
Keywords: aldehyde dehydrogenase
beta catenin
caspase 3
caspase 7
diosgenin
glycogen synthase kinase 3beta
Hermes antigen
reactive oxygen metabolite
secreted frizzled related protein 4
Wnt protein
antiangiogenic activity
antineoplastic activity
antiproliferative activity
apoptosis
Article
breast cancer cell line
cancer inhibition
cancer stem cell
cell cycle checkpoint
cell self-renewal
chick
controlled study
drug efficacy
embryo
epithelial mesenchymal transition
G0 phase cell cycle checkpoint
gene expression
loss of function mutation
migration inhibition
nonhuman
protein expression
Wnt signaling pathway
Issue Date: 2017
Citation: Bhuvanalakshmi, G, Basappa, Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore, India, Rangappa, K.S, Dharmarajan, A, Sethi, G, Kumar, A.P, Warrier, S (2017). Breast cancer stem-like cells are inhibited by diosgenin, a steroidal saponin, by the attenuation of the Wnt β-catenin signaling via the Wnt antagonist secreted frizzled related protein-4. Frontiers in Pharmacology 8 (MAR) : 124. ScholarBank@NUS Repository. https://doi.org/10.3389/fphar.2017.00124
Rights: Attribution 4.0 International
Abstract: Background: Identification of breast cancer stem cells as the chemo-resistant and tumor-initiating population represents an important milestone in approaching anticancer therapies. Targeting this minor subpopulation of chemo- and radio-resistant stem-like cells, termed as the cancer stem cells (CSCs) and their eradication could significantly enhance clinical outcomes. Most of the presently administered chemotherapeutics target the tumor bulk but are ineffective against the CSCs. We report here that diosgenin (DG), a naturally occurring steroidal saponin, could effectively inhibit CSCs from three breast cancer cell lines, MCF7, T47D and MDA-MB-231, by inducing apoptosis and inhibiting the CSC associated phenotypes. Methods: CSCs were enriched in these cells lines, characterized for CSC traits by immunocytochemistry and flow cytometry. Proliferation and apoptosis assays were performed in these breast CSCs in the presence of DG to obtain the inhibitory concentration. Apoptosis was confirmed with gene expression analysis, Western blotting and propidium iodide staining. TCF-LEF reporter assay, sFRP overexpression and RNAi silencing studies were performed to study regulation of the Wnt pathway. Statistical significance was evaluated by a two-sided Student's t-test. Results: Using the TCF-LEF reporter system, we show the effect of DG on CSCs is predominantly through the network regulating CSC self renewal, the Wnt β-catenin pathway. Specifically, the Wnt antagonist, the secreted frizzled related protein 4, (sFRP4), had a defining role in the action of DG. Gain-of-function of sFRP4 in CSCs could improve the response to DG wherein CSC mediators were inhibited, β-catenin was down regulated and the effectors of epithelial to mesenchymal transition and pro-invasive markers were repressed. Conversely, the loss-of-function of sFRP4 had a reverse effect on the CSC population which therein became enriched, their response to DG treatment was modest, β-catenin levels increased, GSK3β expression decreased and the expression of epithelial markers of CSC was completely abrogated. Conclusion: These findings demonstrate the effect of DG on inhibiting the resilient breast CSCs which could provide a benchmark for the development of DG-based therapies in breast cancer treatment. © 2017 Bhuvanalakshmi, Basappa, Rangappa, Dharmarajan, Sethi, Kumar and Warrier.
Source Title: Frontiers in Pharmacology
URI: https://scholarbank.nus.edu.sg/handle/10635/181291
ISSN: 16639812
DOI: 10.3389/fphar.2017.00124
Rights: Attribution 4.0 International
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