CD44high/ESAlow squamous cell carcinoma cell-derived prostaglandin E2 confers resistance to 5-fluorouracil-induced apoptosis in CD44high/ESAhigh cells.
CD44high/ESAlow squamous cell carcinoma cell-derived prostaglandin E2 confers resistance to 5-fluorouracil-induced apoptosis in CD44high/ESAhigh cells.
复制标题
DOI：
--
复制
发表时间：
2018-05
影响因子：
1.4
通讯作者：
H. Shigeishi;Miho Hashikata;Sho Yokoyama;Miyuki Sakuma;Hiroshi Murozumi;Hiroki Kato;M. Z. Rahman;Sayaka Seino;Y. Ishioka;K. Ohta;M. Takechi;M. Sugiyama
中科院分区：
文献类型：
--
作者：
H. Shigeishi;Miho Hashikata;Sho Yokoyama;Miyuki Sakuma;Hiroshi Murozumi;Hiroki Kato;M. Z. Rahman;Sayaka Seino;Y. Ishioka;K. Ohta;M. Takechi;M. Sugiyama
我们先前发现，高表达二氢嘧啶脱氢酶(DPD)的CD44High/ESA低头颈部鳞状细胞癌(HNSCC)细胞对5-氟尿嘧啶(5-FU)诱导的细胞凋亡具有很强的抵抗力。此外，在环氧合酶2(COX2)衍生的前列腺素E2(PGE2)存在的情况下，HNSCC细胞对5-FU的敏感性受到影响。在这项研究中，我们检测了5-FU诱导HNSCC细胞系A-253中CD44High/ESAlow、CD44High/ESAlow和CD44low细胞的凋亡，以阐明PGE2对CD44High细胞的抗凋亡作用。值得注意的是，与其他人群相比，CD44High/ESAlow细胞上调了PGE2。为探讨CD44High/ESAlow细胞来源的PGE2对CD44High/ESAHigh细胞的影响，采用直接共培养和间接共培养方法。CD44High/ESAHigh细胞直接或间接与CD44High/ESAlow细胞共培养后，细胞凋亡率明显降低。此外，在PGE2受体抑制剂EP1/EP2存在下，CD44High/ESAHigh细胞与CD44High/ESAlow细胞共同培养时，5-FU诱导的CD44High/ESAHigh细胞的凋亡率显著增加。提示CD44High/ESAlow细胞来源的PGE2可能参与抑制5-FU诱导的CD44High/ESAHigh细胞的凋亡。此外，NR4A2基因敲除增强了5-FU诱导的CD44High/ESAHigh细胞的凋亡，提示PGE2以NR4A2依赖的方式减弱了5-FU诱导的CD44High/ESAHigh细胞的凋亡。综上所述，CD44High/ESAlow细胞通过提供PGE2诱导CD44High/ESAHigh细胞对5-FU的耐药。CD44High/ESAlow细胞靶向治疗HNSCC可能是有效的。
We previously found that CD44high/ESAlow head and neck squamous cell carcinoma (HNSCC) cells harboring high dihydropyrimidine dehydrogenase (DPD) expression exhibited potent resistance to 5-fluorouracil (5-FU)-induced apoptosis. In addition, susceptibility of HNSCC cells to 5-FU was compromised in the presence of cyclooxygenase 2 (COX2)-derived prostaglandin E2 (PGE2). In this study, we examined 5-FU-induced apoptosis in sorted cell populations (i.e., CD44high/ESAlow, CD44high/ESAhigh, and CD44low cells from the HNSCC cell line A-253) to clarify the anti-apoptotic effect of PGE2 on CD44high cells. Notably, CD44high/ESAlow cells upregulated PGE2, compared with other populations. To investigate the effect of CD44high/ESAlow cell-derived PGE2 on CD44high/ESAhigh cells, direct and indirect co-culture assays were performed. The percentage of apoptotic cells in a culture of CD44high/ESAhigh cells was significantly reduced when they were directly and indirectly co-cultured with CD44high/ESAlow cells. Furthermore, 5-FU-induced apoptosis of CD44high/ESAhigh cells was significantly increased in the presence of an inhibitor of the PGE2 receptors (EP1/EP2) when CD44high/ESAhigh cells were co-cultured with CD44high/ESAlow cells. These results suggest that CD44high/ESAlow cell-derived PGE2 may contribute to the inhibition of 5-FU-induced apoptosis in CD44high/ESAhigh cells. Additionally, NR4A2 knockdown enhances 5-FU-induced apoptosis in CD44high/ESAhigh cells, suggesting that PGE2 attenuates 5-FU-induced apoptosis in an NR4A2-dependent manner in CD44high/ESAhigh cells. In conclusion, CD44high/ESAlow cells contribute to induction of resistance to 5-FU in CD44high/ESAhigh cells through provision of PGE2. CD44high/ESAlow cell-targeted therapy may be effective in treatment of HNSCC.