Bufalin Induces Mitochondria-Dependent Apoptosis in Pancreatic and Oral Cancer Cells by Downregulating hTERT Expression via Activation of the JNK/p38 Pathway.
Bufalin Induces Mitochondria-Dependent Apoptosis in Pancreatic and Oral Cancer Cells by Downregulating hTERT Expression via Activation of the JNK/p38 Pathway.
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Bufalin 通过激活 JNK/p38 通路下调 hTERT 表达，诱导胰腺癌细胞和口腔癌细胞发生线粒体依赖性细胞凋亡。
DOI：
10.1155/2015/546210
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Jiang Y
中科院分区：
文献类型：
--
作者：
Tian X;Dai S;Sun J;Jiang S;Sui C;Meng F;Li Y;Fu L;Jiang T;Wang Y;Su J;Jiang Y
蟾毒灵是中药禅素中的一种类似地高辛的活性成分，在许多人类癌症中显示出有效的抗肿瘤活性。蟾毒灵诱导癌细胞线粒体依赖性凋亡，但详细的分子机制在很大程度上是未知的。端粒酶的催化亚基hTERT通过结合线粒体DNA和减少线粒体ROS的产生来保护线粒体免受损伤。在本研究中，我们研究了蟾毒灵对CAPAN-2人胰腺癌细胞和CAL-27人口腔癌细胞的细胞活力、ROS生成、DNA损伤和凋亡的影响。蟾毒灵降低CAPAN-2和CAL-27细胞活力，ic50值分别为159.2 nM和122.6 nM。细胞活力降低，ROS生成增加，DNA损伤，细胞凋亡，hTERT表达降低。siRNA对CAPAN-2和CAL-27细胞的hTERT沉默导致caspase-9/-3切割和DNA损伤增加，细胞活力降低。综上所述，这些数据表明蟾毒灵下调hTERT以诱导CAPAN-2和CAL-27细胞线粒体依赖性凋亡。此外，蟾毒灵增加了CAPAN-2和CAL-27细胞中JNK和p38-MAPK的磷酸化，使用JNK抑制剂SP600125或p38-MAPK抑制剂SB203580阻断JNK/p38-MAPK通路可逆转蟾毒灵诱导的hTERT下调。因此，JNK/p38途径参与了蟾毒灵诱导的hTERT下调以及随后通过线粒体途径诱导细胞凋亡。
Bufalin, a digoxin-like active component of the traditional Chinese medicine Chan Su, exhibits potent antitumor activities in many human cancers. Bufalin induces mitochondria-dependent apoptosis in cancer cells, but the detailed molecular mechanisms are largely unknown. hTERT, the catalytic subunit of telomerase, protects against mitochondrial damage by binding to mitochondrial DNA and reducing mitochondrial ROS production. In the present study, we investigated the effects of bufalin on the cell viability, ROS production, DNA damage, and apoptosis of CAPAN-2 human pancreatic and CAL-27 human oral cancer cells. Bufalin reduced CAPAN-2 and CAL-27 cell viability with IC50values of 159.2 nM and 122.6 nM, respectively. The reduced cell viability was accompanied by increased ROS production, DNA damage, and apoptosis and decreased expression of hTERT. hTERT silencing in CAPAN-2 and CAL-27 cells by siRNA resulted in increased caspase-9/-3 cleavage and DNA damage and decreased cell viability. Collectively, these data suggest that bufalin downregulates hTERT to induce mitochondria-dependent apoptosis in CAPAN-2 and CAL-27 cells. Moreover, bufalin increased the phosphorylation of JNK and p38-MAPK in CAPAN-2 and CAL-27 cells, and blocking the JNK/p38-MAPK pathway using the JNK inhibitor SP600125 or the p38-MAPK inhibitor SB203580 reversed bufalin-induced hTERT downregulation. Thus, the JNK/p38 pathway is involved in bufalin-induced hTERT downregulation and subsequent induction of apoptosis by the mitochondrial pathway.