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Open Access Highly Accessed Research article

Salinomycin induces cell death and differentiation in head and neck squamous cell carcinoma stem cells despite activation of epithelial-mesenchymal transition and Akt

Selena Z Kuo1, Katherine J Blair1, Elham Rahimy1, Alan Kiang1, Eric Abhold1, Jian-Bing Fan2, Jessica Wang-Rodriguez3, Xabier Altuna4 and Weg M Ongkeko1*

Author affiliations

1 Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, San Diego, San Diego, CA, USA

2 Illumina Inc., San Diego, CA, 92121, USA

3 Veterans Administration Medical Center and Department of Pathology, University of California, San Diego, La Jolla, CA, USA

4 Hospital Universitario Donostia, San Sebastian, Spain

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Citation and License

BMC Cancer 2012, 12:556  doi:10.1186/1471-2407-12-556

Published: 24 November 2012

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.

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.

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.

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.

Keywords:
Salinomycin; Cancer stem cells; Head and neck squamous cell carcinoma; Akt; EMT; microRNA