Elevation in 5-FU-induced apoptosis in Head and Neck Cancer Stem Cells by a combination of CDHP and GSK3β inhibitors

Autor: Sayaka Seino, Masaru Sugiyama, Adrian Biddle, Miho Yamasaki, Ian C. Mackenzie, Luke Gammon, Camila Oliveira Rodini, Masaaki Takechi, Hideo Shigeishi
Rok vydání: 2014
Předmět:
Antimetabolites
Antineoplastic
Cancer Research
Pathology
medicine.medical_specialty
Epithelial-Mesenchymal Transition
CD3 Complex
Pyridines
Population
Apoptosis
Cell Separation
Epithelium
Pathology and Forensic Medicine
Glycogen Synthase Kinase 3
Antigens
Neoplasm
Cancer stem cell
Cell Line
Tumor
hemic and lymphatic diseases
Biomarkers
Tumor
medicine
Humans
Epithelial–mesenchymal transition
education
Dihydrouracil Dehydrogenase (NADP)
education.field_of_study
Glycogen Synthase Kinase 3 beta
biology
CD44
Mesenchymal stem cell
Cell Differentiation
Epithelial Cell Adhesion Molecule
Flow Cytometry
medicine.disease
Head and neck squamous-cell carcinoma
Hyaluronan Receptors
Otorhinolaryngology
Drug Resistance
Neoplasm
Head and Neck Neoplasms
Neoplastic Stem Cells
biology.protein
Cancer research
Periodontics
Fluorouracil
Oral Surgery
Stem cell
Cell Adhesion Molecules
Zdroj: Journal of Oral Pathology & Medicine. 44:201-207
ISSN: 0904-2512
DOI: 10.1111/jop.12230
Popis: Background Cancer 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 et al., 2011). CSCs are resistant to therapeutically induced apoptosis but the molecular mechanisms by which they develop apoptotic resistance remains unclear. However, glycogen synthase kinase 3β (GSK3β) contributes to regulation of both the self-renewal and switching of these two CSC phenotypes (Shigeishi et al., 2013). Methods CD44(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. Results CD44(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 GSK3β 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 GSK3β inhibitors markedly enhanced 5-FU-induced apoptosis of CD44(high) /ESA(low) cells. Conclusions Our results suggest potentially new approaches for the elimination of the therapy resistant HNSCC CSC population.
Databáze: OpenAIRE
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