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2017 ; 8
(ä): 124
Nephropedia Template TP
gab.com Text
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English Wikipedia
Breast Cancer Stem-Like Cells Are Inhibited by Diosgenin, a Steroidal Saponin, by
the Attenuation of the Wnt ?-Catenin Signaling via the Wnt Antagonist Secreted
Frizzled Related Protein-4
#MMPMID28373842
Bhuvanalakshmi G
; Basappa
; Rangappa KS
; Dharmarajan A
; Sethi G
; Kumar AP
; Warrier S
Front Pharmacol
2017[]; 8
(ä): 124
PMID28373842
show ga
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 ?-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, ?-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, ?-catenin levels increased, GSK3? 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.