Journal
JOURNAL OF ORAL PATHOLOGY & MEDICINE
Volume 44, Issue 3, Pages 201-207Publisher
WILEY
DOI: 10.1111/jop.12230
Keywords
5-FU; cancer stem cell; GSK3; head and neck squamous cell carcinoma
Categories
Funding
- Scientific Research Fund of Sugiyama Chemical and Industrial Laboratory
- Satake Fund for Scientific Research from Hiroshima University Supporters' Association
- Japanese Ministry of Education, Culture, Sports, and Technology [11008667]
- NC3Rs
- Barts and The London Charitable Foundation
- Grants-in-Aid for Scientific Research [26463005] Funding Source: KAKEN
- National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) [G0900799/1, NC/L00061X/1, NC/K500495/1] Funding Source: researchfish
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BackgroundCancer stem cells (CSCs) are involved in both tumourigenesis and in tumour recurrence after therapy. In head and neck squamous cell carcinoma (HNSCC), there are two biologically different CSC phenotypes both of which express high levels of CD44 but differ in their expression levels of epithelial-specific antigen (ESA). One phenotype is CD44(high)/ESA(high) and has epithelial features (Epi-CSCs), while the other is CD44(high)/ESA(low), has undergone epithelial to mesenchymal transition (EMT-CSCs), has mesenchymal features and is migratory (Biddle etal., 2011). CSCs are resistant to therapeutically induced apoptosis but the molecular mechanisms by which they develop apoptotic resistance remains unclear. However, glycogen synthase kinase 3 (GSK3) contributes to regulation of both the self-renewal and switching of these two CSC phenotypes (Shigeishi etal., 2013). MethodsCD44(high)/ESA(low), CD44(high)/ESA(high) and CD44(low) cells were FACS sorted from the HNSCC cell line LUC4, and 5-FU-induced apoptosis was analysed by Annexin V staining followed by flow cytometry analysis. ResultsCD44(high)/ESA(low) cells exhibited marked resistance to 5-FU-induced apoptosis and had high expression of dihydropyrimidine dehydrogenase (DPD). The DPD inhibitor, 5-chloro-2, 4-dihydroxypyridine (CDHP) significantly enhanced 5-FU-induced apoptosis of CD44(high)/ESA(low) cells. Inhibition of GSK3 induced CD44(high)/ESA(low) cells to undergo mesenchymal-to-epithelial transition (MET) to CD44(high)/ESA(high) cells and pre-existing CD44(high)/ESA(high) cells to differentiate. Apoptosis induced by 5-FU was thus facilitated. Combination of both CDHP and GSK3 inhibitors markedly enhanced 5-FU-induced apoptosis of CD44(high)/ESA(low) cells. ConclusionsOur results suggest potentially new approaches for the elimination of the therapy resistant HNSCC CSC population.
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