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

BMC Cancer

Research Article

Weg M Ongkeko¹  Selena Z Kuo¹  Katherine J Blair¹  Eric Abhold¹  Elham Rahimy¹  Alan Kiang¹  Xabier Altuna²  Jian-Bing Fan³  Jessica Wang-Rodriguez⁴ 

[1] Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, University of California, San Diego, San Diego, CA, USA;Hospital Universitario Donostia, San Sebastian, Spain;Illumina Inc., 92121, San Diego, CA, USA;Veterans Administration Medical Center and Department of Pathology, University of California, San Diego, La Jolla, CA, USA;

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

DOI  :  10.1186/1471-2407-12-556

 received in 2012-06-19, accepted in 2012-11-21,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundCancer 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.MethodsMTS 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.ResultsIn 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.ConclusionsThese 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.

【 授权许可】

Unknown   
© Kuo et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.