Lanatoside C, a Cardiac Glycoside, Acts Through Protein Kinase Cδ to Cause Apoptosis of Human Hepatocellular Carcinoma Cells

Overview

Journal Sci Rep

Specialty Science

Date 2017 Apr 8

PMID 28387249

Citations 20

Authors

Min-Wu Chao

Tzu-Hsuan Chen

Han-Li Huang

Yu-Wei Chang

Wei-Chun HuangFu

Yu-Ching Lee

Che-Ming Teng

Shiow-Lin Pan

Affiliations

Soon will be listed here.

Abstract

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.

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