Abstract
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.
Highlights
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
To further verify the stem cell phenotype of the JLO-1 culture, a qPCR was performed to evaluate the expression of aldehyde dehydrogenase class-1A1 (ALDH1A1) and the transcription factors Oct-4 and Nanog in JLO-1 relative to a head and neck squamous cell carcinoma (HNSCC) cell line, UMSCC-10B, cultured under standard conditions
Previous studies indicate ALDH is a more specific HNSCC CSC marker than CD44, as ALDH expression identifies a subpopulation of CD44 positive cells containing the tumorigenic cancer stem cells [22,23]
Summary
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. Gupta et al used a high throughput screening to identify drugs that could potentially be used to target breast CSCs. By using a novel method of screening, approximately 16,000 compounds were evaluated for their ability to eradicate breast CSCs. By using a novel method of screening, approximately 16,000 compounds were evaluated for their ability to eradicate breast CSCs This screening revealed that the compound salinomycin was able to kill breast CSCs 100-fold more effectively than paclitaxel [5]. The antibiotic properties of salinomycin are well known, but its potential to eradicate CSCs in other cancer types needs to be further elucidated
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