TY - JOUR
T1 - Celastrol induces apoptosis in hepatocellular carcinoma cells via targeting ER-stress/UPR
AU - Ren, Bo
AU - Liu, Hui
AU - Gao, Hang
AU - Liu, Shutong
AU - Zhang, Zehui
AU - Fribley, Andrew M.
AU - Callaghan, Michael U.
AU - Xu, Zhixiang
AU - Zeng, Qinghua
AU - Li, Yulin
N1 - Funding Information:
These studies were supported by the National Natural Science Foundation of China grants #81272243 and #81271853. Portions of this work were also supported by NIH grant CA 108741. Portions of these studies were supported by NIH grants R00 DE019678 and R03 MH089787, the Children’s Hospital of Michigan Foundation and the Wayne State University Fund for Medical Research (AMF). We would like to thank Joshua Fried for helping with editing the manuscript.
Publisher Copyright:
© Ren et al.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Autophagy
KW - Celastrol
KW - ER stress
KW - Hepatocellular carcinoma
UR - http://www.scopus.com/inward/record.url?scp=85032702590&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.21750
DO - 10.18632/oncotarget.21750
M3 - Article
AN - SCOPUS:85032702590
SN - 1949-2553
VL - 8
SP - 93039
EP - 93050
JO - Oncotarget
JF - Oncotarget
IS - 54
ER -