Niclosamide induced cell apoptosis via upregulation of ATF3 and activation of PERK in Hepatocellular carcinoma cells.

Shunyan Weng,Jiaxian Wang,Jianwei Zhu,Qing Deng,Yunsheng Yuan,Yan Yu,Liang Zhou

doi:10.1186/s12876-016-0442-3

Shunyan Weng, Jiaxian Wang + Show 5 more

Open Access

https://doi.org/10.1186/s12876-016-0442-3

Copy DOI

Journal: BMC gastroenterology	Publication Date: Feb 25, 2016
Citations: 57	License type: cc-by

Affiliation: Shanghai Jiao Tong University

Abstract

BackgroundHepatocellular carcinoma (HCC) is one of most common and aggressive human malignancies in the world, especially, in eastern Asia, and its mortality is very high at any phase. We want to investigate mechanism of niclosamide inducing cell apoptosis in HCC.MethodsTwo hepatoma cell lines were used to evaluate activity of niclosamide inducing cell apoptosis and study its mechanism. Quantitative real-time PCR and western blotting were used in analysis of genes expression or protein active regulated by niclosamide.ResultsNiclosamide remarkably induced cell apoptosis in hepatoma cells. Furthermore, our study revealed that RNA-dependent protein kinase-like kinase (PERK) is activated and its expression is up-regulated in HCC cells which are exposed to niclosamide. niclosamide also significantly increase activating transcription factor 3 (ATF3), activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-homologous protein (CHOP) expression in HCC cells. It’s suggested that the function of niclosamide was abrogated by PERK inhibitor or absent ATF3. Expression of PERK and CHOP is correlated with ATF3 level in the cells.ConclusionTaken together, our results indicate that ATF3 plays an integral role in ER stress activated and cell apoptosis induced by niclosamide in HCC cells. In this study, the new mechanism of niclosamide as anti-cancer we investigated, too.

Highlights

Hepatocellular carcinoma (HCC) is one of most common and aggressive human malignancies in the world, especially, in eastern Asia, and its mortality is very high at any phase
The expression of activating transcription factor 3 (ATF3), activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein-homologous protein (CHOP) were analyzed with room temperature (RT)-PCR and results showed that all of their mRNA levels were remarkably increased after niclosamide treatment (Fig. 2b, c, d)
To identify whether protein kinase RNA like ER kinase (PERK) pathway is activated by niclosamide, different doses of niclosamide was used to treat hepatoma cells and certain protein levels were analyzed with western blotting

Summary

Introduction

Hepatocellular carcinoma (HCC) is one of most common and aggressive human malignancies in the world, especially, in eastern Asia, and its mortality is very high at any phase. Hepatocellular carcinoma (HCC) is one of the most common and aggressive human malignancies in the world [1] It is a major public health issue worldwide according to epidemiological data, and the incidence is high in East Asia. It is well known that Endoplasmic Reticulum (ER) stress could induce cell apoptosis or cell death in many tumor categories, including breast cancer [4], neuroectodermal tumor [5], HCC [6], etc. CCAAT/enhancer-binding protein-homologous protein (CHOP, known as GADD153), a downstream element to ATF4 in the PERK pathway, induces apoptosis or cell death under intensive or prolonged ER stress conditions [9, 10]. Other data showed that niclosamide, an antihelminthic drug for treatment of tapeworm infections approved by FDA, has exhibited anticancer function in different tumor types, including leukemia, colon cancer, glioma, etc [15]. We demonstrated a new mechanism of niclosamide as anticancer with HCC cells

Methods

Results

Discussion

Conclusion