Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma
Abstract Background Xanthoangelol (XAG) was reported to exhibit antitumor properties in several cancer. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC) and the relevant mechanisms are not known. Methods The effects of XAG on HCC cell proliferation and apoptos...
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doaj-34984d6b51ed428282dde58122878e8b2020-11-25T01:37:10ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662019-01-0138111610.1186/s13046-018-1012-zEndoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinomaZichao Li0Luying Zhang1Mingquan Gao2Mei Han3Kaili Liu4Zhuang Zhang5Zhi Gong6Lifei Xing7Xianzhou Shi8Kui Lu9Hui Gao10College of Life Sciences, Qingdao UniversityDepartment of Pharmacology, School of Pharmacy, Qingdao UniversityThe Affiliated Cancer Hospital, School of Medicine, University of Electronic Science and Technology of ChinaDepartment of Pharmacology, School of Pharmacy, Qingdao UniversityDepartment of Pharmacology, School of Pharmacy, Qingdao UniversityChina International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & TechnologyChina International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & TechnologyDepartment of Pharmacology, School of Pharmacy, Qingdao UniversityNortheast Yucai Bilingual SchoolChina International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & TechnologyDepartment of Pharmacology, School of Pharmacy, Qingdao UniversityAbstract Background Xanthoangelol (XAG) was reported to exhibit antitumor properties in several cancer. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC) and the relevant mechanisms are not known. Methods The effects of XAG on HCC cell proliferation and apoptosis were respectively examined by CCK-8 assay and Annexin V-FITC/PI apoptosis kit. Western blotting was conducted to detect the expression of proteins. The effect of XAG on the development of acidic vesicle organelles was assessed using acridine orange staining. mRFP-GFP-LC3 adenovirus was used to transfect HCC cells and the formation of autolysosome was detected using a confocal microscope. Results Mechanistically, XAG promotes HCC cell death through triggering intrinsic apoptosis pathway, not extrinsic apoptotic pathway. Furthermore, XAG treatment induced autophagy in Bel 7402 and SMMC 7721 cells, as evidenced by an increase in autophagy-associated proteins, including LC3B-II, Beclin-1, and Atg5. Interestingly, inhibition of autophagy with 3-MA, Bafilomycin A1 (Baf A1), or siRNA targeting Atg5 effectively enhanced the apoptotic cell ratio in XAG-treated cells, indicating that protective effect of autophagy induced by XAG in HCC. Moreover, autophagy induced by XAG was mediated by activating endoplasmic reticulum stress (ERS), along with administration of XAG, the expression levels of ERS-associated proteins, including CHOP, GRP78, ATF6, p-eIF2α, IRE1α, and cleaved caspase-12 were significantly increased in HCC cells. Meanwhile, suppressing ERS with chemical chaperones (TUDCA) or CHOP shRNA could effectively abrogate the autophagy-inducing effect of XAG, and increase the apoptotic cell death. Further mechanistic studies showed that ERS-induced autophagy in XAG-treated cells was mediated by activation of JNK/c-jun pathway. XAG treatment resulted in the increase of p-JNK and p-c-jun, while suppressing ERS with TUDCA or CHOP shRNA could effectively reverse it. Meanwhile, SP600125, a JNK inhibitor, effectively reversed XAG-induced protective autophagy and enhanced cell apoptosis in XAG-treated HCC cells. In vivo results demonstrated that XAG exerts potent antitumor properties with low toxicity. Conclusions Collectively, these results suggested that XAG could be served as a promising candidate for the treatment and prevention of HCC.http://link.springer.com/article/10.1186/s13046-018-1012-zXAGApoptosisAutophagyER stressHCC |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zichao Li Luying Zhang Mingquan Gao Mei Han Kaili Liu Zhuang Zhang Zhi Gong Lifei Xing Xianzhou Shi Kui Lu Hui Gao |
spellingShingle |
Zichao Li Luying Zhang Mingquan Gao Mei Han Kaili Liu Zhuang Zhang Zhi Gong Lifei Xing Xianzhou Shi Kui Lu Hui Gao Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma Journal of Experimental & Clinical Cancer Research XAG Apoptosis Autophagy ER stress HCC |
author_facet |
Zichao Li Luying Zhang Mingquan Gao Mei Han Kaili Liu Zhuang Zhang Zhi Gong Lifei Xing Xianzhou Shi Kui Lu Hui Gao |
author_sort |
Zichao Li |
title |
Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma |
title_short |
Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma |
title_full |
Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma |
title_fullStr |
Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma |
title_full_unstemmed |
Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma |
title_sort |
endoplasmic reticulum stress triggers xanthoangelol-induced protective autophagy via activation of jnk/c-jun axis in hepatocellular carcinoma |
publisher |
BMC |
series |
Journal of Experimental & Clinical Cancer Research |
issn |
1756-9966 |
publishDate |
2019-01-01 |
description |
Abstract Background Xanthoangelol (XAG) was reported to exhibit antitumor properties in several cancer. However, the specific anti-tumor activity of XAG in human hepatocellular carcinoma (HCC) and the relevant mechanisms are not known. Methods The effects of XAG on HCC cell proliferation and apoptosis were respectively examined by CCK-8 assay and Annexin V-FITC/PI apoptosis kit. Western blotting was conducted to detect the expression of proteins. The effect of XAG on the development of acidic vesicle organelles was assessed using acridine orange staining. mRFP-GFP-LC3 adenovirus was used to transfect HCC cells and the formation of autolysosome was detected using a confocal microscope. Results Mechanistically, XAG promotes HCC cell death through triggering intrinsic apoptosis pathway, not extrinsic apoptotic pathway. Furthermore, XAG treatment induced autophagy in Bel 7402 and SMMC 7721 cells, as evidenced by an increase in autophagy-associated proteins, including LC3B-II, Beclin-1, and Atg5. Interestingly, inhibition of autophagy with 3-MA, Bafilomycin A1 (Baf A1), or siRNA targeting Atg5 effectively enhanced the apoptotic cell ratio in XAG-treated cells, indicating that protective effect of autophagy induced by XAG in HCC. Moreover, autophagy induced by XAG was mediated by activating endoplasmic reticulum stress (ERS), along with administration of XAG, the expression levels of ERS-associated proteins, including CHOP, GRP78, ATF6, p-eIF2α, IRE1α, and cleaved caspase-12 were significantly increased in HCC cells. Meanwhile, suppressing ERS with chemical chaperones (TUDCA) or CHOP shRNA could effectively abrogate the autophagy-inducing effect of XAG, and increase the apoptotic cell death. Further mechanistic studies showed that ERS-induced autophagy in XAG-treated cells was mediated by activation of JNK/c-jun pathway. XAG treatment resulted in the increase of p-JNK and p-c-jun, while suppressing ERS with TUDCA or CHOP shRNA could effectively reverse it. Meanwhile, SP600125, a JNK inhibitor, effectively reversed XAG-induced protective autophagy and enhanced cell apoptosis in XAG-treated HCC cells. In vivo results demonstrated that XAG exerts potent antitumor properties with low toxicity. Conclusions Collectively, these results suggested that XAG could be served as a promising candidate for the treatment and prevention of HCC. |
topic |
XAG Apoptosis Autophagy ER stress HCC |
url |
http://link.springer.com/article/10.1186/s13046-018-1012-z |
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