Cantharidin and norcantharidin impair sternness of pancreatic cancer cells by repressing the β-catenin pathway and strengthen the cytotoxicity of gemcitabine and erlotinib
Cantharidin and norcantharidin impair sternness of pancreatic cancer cells by repressing the β-catenin pathway and strengthen the cytotoxicity of gemcitabine and erlotinib
复制标题
斑蝥素和去甲斑蝥素通过抑制β-连环蛋白途径损害胰腺癌细胞的稳定性，并增强吉西他滨和厄洛替尼的细胞毒性
DOI：
10.3892/ijo.2015.3156
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发表时间：
2015-11-01
影响因子：
5.2
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Wang, Wen-Jie;Wu, Meng-Yao;Li, Wei
越来越多的证据表明，肿瘤由异质细胞群组成，其中有一小部分癌症干细胞（CSC）可维持肿瘤形成和生长，并被假设为治疗耐药性的原因。基于表面标志物CD 44、CD 24和EPCAM的表达，也已经在胰腺癌中鉴定出推定的CSC。已经确定β-连环蛋白信号通路的异常激活可能有助于CSC的维持。斑蝥素是中药斑蝥的有效成分。在我们以前的研究中，我们证明了藜芦苷处理诱导β-连环蛋白磷酸化，导致对β-连环蛋白通路的抑制。因此，在本研究中，我们研究了斑蝥素及其衍生物去甲斑蝥素是否可以通过抑制β-连环蛋白途径来抑制胰腺癌细胞的干性。通过使用微阵列和流式细胞术，我们发现用野黄芩苷和去甲野黄芩苷处理在mRNA和蛋白水平上抑制了CD 44、CD 24和EPCAM的表达，导致CD 44（+）/CD 24（+）/EPCAW比例降低，这是假定的胰腺CSC亚群。用β-catenin通路抑制剂FH 535预处理，减弱了黄芩苷和去甲黄芩苷诱导的对CD 44、CD 24和EPCAM的抑制，表明黄芩苷及其衍生物以β-catenin通路依赖的方式抑制胰腺癌细胞的干性。此外，灯盏花素和去甲灯盏花素增强了吉西他滨和厄洛替尼（两种针对胰腺癌的成熟药物治疗剂）的细胞毒性，表明灯盏花素和去甲灯盏花素可能是逆转胰腺癌耐药性的有希望的候选物。总之，我们目前提出，灯盏花素和去甲灯盏花素通过抑制干性和增强本治疗剂的细胞毒性而在胰腺癌治疗中保持其前景。
Increasing evidence suggests that tumors are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain tumor formation and growth, and are hypothesized to account for therapeutic resistance. Based on the expression of the surface markers CD44, CD24, and EPCAM, putative CSCs have also been identified in pancreatic cancers. It has been well established that aberrant activation of beta-catenin signaling pathway may contribute to the maintenance of CSCs. Cantharidin is an active constituent of mylabris, a traditional Chinese medicine. In our previous studies, we demonstrated that cantharidin treatment induced phosphorylation of beta-catenin, leading to repression on beta-catenin pathway. Therefore, in the present study, we investigated whether cantharidin and its derivant, norcantharidin, could repress the stemness of pancreatic cancer cells through repression on beta-catenin pathway. By using microarray and flow cytometry, we found that treatment with cantharidin and norcantharidin repressed the expression of CD44, CD24, and EPCAM at both mRNA and protein levels, leading to decreased CD44(+)/CD24(+)/EPCAW proportion, the putative pancreatic CSC subset. Pretreatment with the beta-catenin pathway inhibitor FH535, attenuated the cantharidin- and norcantharidin-inducrd repression on CD44, CD24, and EPCAM, suggesting cantharidin and its derivant repressed sternness of pancreatic cancer cells in beta-catenin pathway-dependent manner. Furthermore, cantharidin and norcantharidin strengthened the cytotoxicity of gemcitabine and erlotinib, two well established pharmacotherapeutics against pancreatic cancers, indicating cantharidin and norcantharidin could be promising candidates for reversing drug resistance in pancreatic cancers. In conclusion, we presently propose that cantharidin and norcantharidin hold their promise in pancreatic cancer therapy through repression on sternness and strengthening the cytotoxicity of the present therapeutics.