Elevation in 5-FU-induced apoptosis in Head and Neck Cancer Stem Cells by a combination of CDHP and GSK3β inhibitors
Elevation in 5-FU-induced apoptosis in Head and Neck Cancer Stem Cells by a combination of CDHP and GSK3β inhibitors
复制标题
DOI：
10.1111/jop.12230
复制
发表时间：
2015-03-01
影响因子：
3.3
通讯作者：
Mackenzie, Ian C.
中科院分区：
文献类型：
--
作者：
Shigeishi, Hideo;Biddle, Adrian;Mackenzie, Ian C.
背景肿瘤干细胞（CSCs）参与肿瘤的发生和治疗后的肿瘤复发.在头颈部鳞状细胞癌（HNSCC）中，存在两种生物学上不同的CSC表型，这两种表型均表达高水平的CD 44，但其上皮特异性抗原（ESA）的表达水平不同。一种表型是CD 44（高）/ESA（高）并且具有上皮特征（Epi-CSC），而另一种表型是CD 44（高）/ESA（低），经历了上皮向间充质转化（EMT-CSC），具有间充质特征并且是迁移性的（Biddle埃塔尔，2011年）。CSC对治疗诱导的细胞凋亡具有抗性，但它们产生细胞凋亡抗性的分子机制仍不清楚。然而，糖原合成酶激酶3（GSK 3）有助于调节这两种CSC表型的自我更新和转换（Shigeishi埃塔尔，方法流式细胞仪分选HNSCC细胞系LUC 4中的CD 44（high）/ESA（low）、CD 44（high）/ESA（high）和CD 44（low）细胞，Annexin V染色后流式细胞术分析5-FU诱导的细胞凋亡。DPD抑制剂5-氯-2，4-二羟基吡啶（5-chloro-2，4-dihydroxypyridine，CDHP）可显著增强5-FU诱导的CD 44（high）/ESA（low）细胞凋亡。GSK 3的抑制诱导CD 44（高）/ESA（低）细胞经历间质-上皮转化（MET）至CD 44（高）/ESA（高）细胞和预先存在的CD 44（高）/ESA（高）细胞以分化。5-FU诱导的细胞凋亡也因此变得容易。CDHP和GSK 3抑制剂的组合显着增强5-FU诱导的CD 44（高）/ESA（低）cells.ConclusionsOur研究结果表明，潜在的新方法消除耐药HNSCC CSC人口的凋亡。
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.