Celastrol induces apoptosis in hepatocellular carcinoma cells via targeting ER-stress/UPR

Bo Ren; Hui Liu; Hang Gao; Shutong Liu; Zehui Zhang; Andrew M. Fribley; Michael U. Callaghan; Zhixiang Xu; Qinghua Zeng; Yulin Li

doi:10.18632/oncotarget.21750

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Research Papers:

Celastrol induces apoptosis in hepatocellular carcinoma cells via targeting ER-stress/UPR

Bo Ren, Hui Liu, Hang Gao, Shutong Liu, Zehui Zhang, Andrew M. Fribley, Michael U. Callaghan, Zhixiang Xu, Qinghua Zeng _ and Yulin Li

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Oncotarget. 2017; 8:93039-93050. https://doi.org/10.18632/oncotarget.21750

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Abstract

Bo Ren1, Hui Liu2, Hang Gao1, Shutong Liu1, Zehui Zhang1, Andrew M. Fribley3,4, Michael U. Callaghan3, Zhixiang Xu1,5, Qinghua Zeng1,5 and Yulin Li1

1The Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun 130021, China

2Pathology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China

3Carman and Ann Adams Department of Pediatrics, Division of Hematology/Oncology, Wayne State University, Detroit, MI 48201, USA

4Molecular Therapeutics Program, Karmanos Cancer Institute, Detroit, MI 48201, USA

5Division of Hematology/Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA

Correspondence to:

Qinghua Zeng, email: [email protected]

Yulin Li, email: [email protected]

Keywords: hepatocellular carcinoma, ER stress, autophagy, celastrol, apoptosis

Received: June 30, 2017 Accepted: August 27, 2017 Published: October 10, 2017

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most serious and deadly diseases worldwide with limited options for effective treatment. Biomarker-based active compound targeting therapy may shed some light on novel drugs for HCC. The endoplasmic reticulum (ER) stress and unfolded protein response (UPR) play important roles in the regulation of cell fate and have become novel signaling targets for the development of anticancer drugs. Celastrol, a triterpene from traditional Chinese medicine, has been reported to possess anti-tumor effects on various cancers. We, along with several other research groups, have recently reported that UPR was induced by celastrol in several different cancers, including hepatocellular carcinoma. However, UPR status in HCC still remains unclear. The role of ER stress and autophagy in response to celastrol also has yet to be elucidated. Our results demonstrated that celastrol could cause G2/M phase rest and inhibit proliferation in HepG2 and Bel7402. Exposure to celastrol resulted in the activation of the intrinsic apoptotic pathway, via ER stress and the UPR. In murine syngeneic model studies celastrol inhibited H22 tumor growth via the induction of ER stress and apoptosis. Our study suggests that celastrol is a potential drug for HCC therapy via targeting ER-stress/UPR.

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Research Papers:

Celastrol induces apoptosis in hepatocellular carcinoma cells via targeting ER-stress/UPR

Abstract