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Salinomycin induces cell death and differentiation in head and neck squamous cell carcinoma stem cells despite activation of epithelial-mesenchymal transition and Akt.
- Source :
-
BMC cancer [BMC Cancer] 2012 Nov 24; Vol. 12, pp. 556. Date of Electronic Publication: 2012 Nov 24. - Publication Year :
- 2012
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Abstract
- Background: Cancer stem cells (CSC) are believed to play a crucial role in cancer recurrence due to their resistance to conventional chemotherapy and capacity for self-renewal. Recent studies have reported that salinomycin, a livestock antibiotic, selectively targets breast cancer stem cells 100-fold more effectively than paclitaxel. In our study we sought to determine the effects of salinomycin on head and neck squamous cell carcinoma (HNSCC) stem cells.<br />Methods: MTS and TUNEL assays were used to study cell proliferation and apoptosis as a function of salinomycin exposure in JLO-1, a putative HNSCC stem cell culture. MTS and trypan blue dye exclusion assays were performed to investigate potential drug interactions between salinomycin and cisplatin or paclitaxel. Stem cell-like phenotype was measured by mRNA expression of stem cell markers, sphere-forming capacity, and matrigel invasion assays. Immunoblotting was also used to determine expression of epithelial-mesenchymal transition (EMT) markers and Akt phosphorylation. Arrays by Illumina, Inc. were used to profile microRNA expression as a function of salinomycin dose.<br />Results: In putative HNSCC stem cells, salinomycin was found to significantly inhibit cell viability, induce a 71.5% increase in levels of apoptosis, elevate the Bax/Bcl-2 ratio, and work synergistically with cisplatin and paclitaxel in inducing cell death. It was observed that salinomycin significantly inhibited sphere forming-capability and repressed the expression of CD44 and BMI-1 by 3.2-fold and 6.2-fold, respectively. Furthermore, salinomycin reduced invasion of HNSCC stem cells by 2.1 fold. Contrary to expectations, salinomycin induced the expression of EMT markers Snail, vimentin, and Zeb-1, decreased expression of E-cadherin, and also induced phosphorylation of Akt and its downstream targets GSK3-β and mTOR.<br />Conclusions: These results demonstrate that in HNSCC cancer stem cells, salinomycin can cause cell death and decrease stem cell properties despite activation of both EMT and Akt.
- Subjects :
- Apoptosis drug effects
Apoptosis genetics
Carcinoma, Squamous Cell genetics
Cell Death drug effects
Cell Death genetics
Cell Differentiation drug effects
Cell Differentiation genetics
Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Cisplatin pharmacology
Drug Interactions
Enzyme Activation drug effects
Epithelial-Mesenchymal Transition genetics
Head and Neck Neoplasms genetics
Humans
Hyaluronan Receptors genetics
MicroRNAs genetics
Mitogen-Activated Protein Kinase 7 genetics
Paclitaxel pharmacology
Phosphorylation drug effects
Proto-Oncogene Proteins c-akt genetics
Proto-Oncogene Proteins c-bcl-2 genetics
RNA, Messenger genetics
Squamous Cell Carcinoma of Head and Neck
bcl-2-Associated X Protein genetics
Carcinoma, Squamous Cell drug therapy
Carcinoma, Squamous Cell pathology
Epithelial-Mesenchymal Transition drug effects
Head and Neck Neoplasms drug therapy
Head and Neck Neoplasms pathology
Neoplastic Stem Cells drug effects
Proto-Oncogene Proteins c-akt metabolism
Pyrans pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1471-2407
- Volume :
- 12
- Database :
- MEDLINE
- Journal :
- BMC cancer
- Publication Type :
- Academic Journal
- Accession number :
- 23176396
- Full Text :
- https://doi.org/10.1186/1471-2407-12-556