Please use this identifier to cite or link to this item: https://doi.org/10.3389/fphar.2017.00124
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dc.titleBreast 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
dc.contributor.authorBhuvanalakshmi, G
dc.contributor.authorBasappa, Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Bangalore, India
dc.contributor.authorRangappa, K.S
dc.contributor.authorDharmarajan, A
dc.contributor.authorSethi, G
dc.contributor.authorKumar, A.P
dc.contributor.authorWarrier, S
dc.date.accessioned2020-10-27T10:28:43Z
dc.date.available2020-10-27T10:28:43Z
dc.date.issued2017
dc.identifier.citationBhuvanalakshmi, 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
dc.identifier.issn16639812
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/181291
dc.description.abstractBackground: 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.
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceUnpaywall 20201031
dc.subjectaldehyde dehydrogenase
dc.subjectbeta catenin
dc.subjectcaspase 3
dc.subjectcaspase 7
dc.subjectdiosgenin
dc.subjectglycogen synthase kinase 3beta
dc.subjectHermes antigen
dc.subjectreactive oxygen metabolite
dc.subjectsecreted frizzled related protein 4
dc.subjectWnt protein
dc.subjectantiangiogenic activity
dc.subjectantineoplastic activity
dc.subjectantiproliferative activity
dc.subjectapoptosis
dc.subjectArticle
dc.subjectbreast cancer cell line
dc.subjectcancer inhibition
dc.subjectcancer stem cell
dc.subjectcell cycle checkpoint
dc.subjectcell self-renewal
dc.subjectchick
dc.subjectcontrolled study
dc.subjectdrug efficacy
dc.subjectembryo
dc.subjectepithelial mesenchymal transition
dc.subjectG0 phase cell cycle checkpoint
dc.subjectgene expression
dc.subjectloss of function mutation
dc.subjectmigration inhibition
dc.subjectnonhuman
dc.subjectprotein expression
dc.subjectWnt signaling pathway
dc.typeArticle
dc.contributor.departmentDEPT OF PHARMACOLOGY
dc.description.doi10.3389/fphar.2017.00124
dc.description.sourcetitleFrontiers in Pharmacology
dc.description.volume8
dc.description.issueMAR
dc.description.page124
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