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Salinomycin induces selective cytotoxicity to MCF-7 mammosphere cells through targeting the Hedgehog signaling pathway.
- Source :
-
Oncology reports [Oncol Rep] 2016 Feb; Vol. 35 (2), pp. 912-22. Date of Electronic Publication: 2015 Nov 17. - Publication Year :
- 2016
-
Abstract
- Breast cancer stem cells (BCSCs) are believed to be responsible for tumor chemoresistance, recurrence, and metastasis formation. Salinomycin (SAL), a carboxylic polyether ionophore, has been reported to act as a selective breast CSC inhibitor. However, the molecular mechanisms underlying SAL-induced cytotoxicity on BCSCs remain unclear. The Hedgehog (Hh) signaling pathway plays an important role in CSC maintenance and carcinogenesis. Here, we investigated whether SAL induces cytotoxicity on BCSCs through targeting Hh pathway. In the present study, we cultured breast cancer MCF-7 cells in suspension in serum-free medium to obtain breast CSC-enriched MCF-7 mammospheres (MCF-7 MS). MCF-7 MS cells possessed typical BCSC properties, such as CD44+CD24-/low phenotype, high expression of OCT4 (a stem cell marker), increased colony-forming ability, strong migration and invasion capabilities, differentiation potential, and strong tumorigenicity in xenografted mice. SAL exhibited selective cytotoxicity to MCF-7 MS cells relative to MCF-7 cells. The Hh pathway was highly activated in BCSC-enriched MCF-7 MS cells and SAL inhibited Hh signaling activation by downregulating the expression of critical components of the Hh pathway such as PTCH, SMO, Gli1, and Gli2, and subsequently repressing the expression of their essential downstream targets including C-myc, Bcl-2, and Snail (but not cyclin D1). Conversely, Shh-induced Hh signaling activation could largely reverse SAL-mediated inhibitory effects. These findings suggest that SAL-induced selective cytotoxicity against MCF-7 MS cells is associated with the inhibition of Hh signaling activation and the expression of downstream targets and the Hh pathway is an important player and a possible drug target in the pathogenesis of BCSCs.
- Subjects :
- Animals
Blotting, Western
Female
Flow Cytometry
Fluorescent Antibody Technique
Humans
MCF-7 Cells
Mice, Inbred BALB C
Mice, Nude
Xenograft Model Antitumor Assays
Antineoplastic Agents pharmacology
Hedgehog Proteins metabolism
Neoplastic Stem Cells drug effects
Pyrans pharmacology
Signal Transduction drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1791-2431
- Volume :
- 35
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Oncology reports
- Publication Type :
- Academic Journal
- Accession number :
- 26718029
- Full Text :
- https://doi.org/10.3892/or.2015.4434