Lanatoside C, a cardiac glycoside, acts through protein kinase Cδ to cause apoptosis of human hepatocellular carcinoma cells.
Lanatoside C, a cardiac glycoside, acts through protein kinase Cδ to cause apoptosis of human hepatocellular carcinoma cells.
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DOI：
10.1038/srep46134
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发表时间：
2017-04-07
影响因子：
4.6
通讯作者：
Pan SL
中科院分区：
文献类型：
--
作者：
Chao MW;Chen TH;Huang HL;Chang YW;HuangFu WC;Lee YC;Teng CM;Pan SL
最近的研究表明，洋地黄和地高辛等强心苷具有抗癌活性，可作为开发癌症治疗的先导化合物。肝细胞癌（HCC）患者的不良预后反映了对当前化疗药物的耐药性的发展，凸显了发现新的小分子疗法的必要性。在此，我们发现毛花苷C（一种从毛地黄中提取的抗心律失常剂）可抑制HCC细胞的生长，并显着减小肿瘤体积并延缓肿瘤生长，而体重却没有明显下降。此外，毛花苷 C 引发线粒体膜电位 (MMP) 损失、半胱天冬酶激活以及凋亡诱导因子 (AIF) 易位到细胞核中，这表明毛花苷 C 通过半胱天冬酶依赖性和不依赖性途径诱导细胞凋亡。此外，我们发现毛花苷 C 通过 Thr505 磷酸化和随后的膜转位激活蛋白激酶 δ (PKCδ)。抑制 PKCδ 可逆转毛花苷 C 诱导的 MMP 丢失和细胞凋亡，证实毛花苷 C 通过 PKCδ 激活引起细胞凋亡。我们还发现 AKT/mTOR 通路受到毛花苷 C 通过 PKCδ 激活的负向调节。总之，我们首次证明毛花苷 C 的抗癌作用主要归因于 PKCδ 激活。
Recent studies have revealed that cardiac glycosides, such as digitalis and digoxin, have anticancer activity and may serve as lead compounds for the development of cancer treatments. The poor prognosis of hepatocellular carcinoma (HCC) patients reflects the development of resistance to current chemotherapeutic agents, highlighting the need for discovering new small-molecule therapeutics. Here, we found that lanatoside C, an anti-arrhythmic agent extracted from Digitalis lanata, inhibited the growth of HCC cells and dramatically decreased tumor volume as well as delayed tumor growth without obvious body weight loss. Moreover, lanatoside C triggered mitochondrial membrane potential (MMP) loss, activation of caspases and translocation of apoptosis-inducing factor (AIF) into the nucleus, which suggests that lanatoside C induced apoptosis through both caspase-dependent and -independent pathways. Furthermore, we discovered that lanatoside C activated protein kinase delta (PKCδ) via Thr505 phosphorylation and subsequent membrane translocation. Inhibition of PKCδ reversed lanatoside C-induced MMP loss and apoptosis, confirming that lanatoside C caused apoptosis through PKCδ activation. We also found that the AKT/mTOR pathway was negatively regulated by lanatoside C through PKCδ activation. In conclusion, we provide the first demonstration that the anticancer effects of lanatoside C are mainly attributable to PKCδ activation.