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18?-Glycyrrhetinic-acid-mediated unfolded protein response induces autophagy and apoptosis in hepatocellular carcinoma.

ABSTRACT: 18?-Glycyrrhetinic acid (GA) is the active ingredient of the traditional Chinese medicine, Glycyrrhrzae Radix et Rhizoma. Here, we explored the effects of GA on hepatocellular carcinoma (HCC) in vitro and in vivo and the underlying molecular mechanisms. We confirmed that GA suppressed proliferation of various HCC cell lines. Treatment of GA caused G0/G1 arrest, apoptosis and autophagy in HCC cells. GA-induced apoptosis and autophagy were mainly due to the unfolded protein response. We compared the roles of the ATF4/CHOP and IRE1?/XBP1s UPR pathways, which were both induced by GA. The ATF4/CHOP cascade induced autophagy and was indispensable for the induction of apoptosis in GA-treated HCC cells. In contrast, the IRE1?/XBP1s cascade protected HCC cells from apoptosis in vitro and in vivo induced by GA. Despite this, activation of autophagy protected HCC cells from apoptosis induced by GA. We concluded that pharmacological inhibition of autophagy or IRE1? may be of benefit to enhance the antitumor activity of GA.

SUBMITTER: Chen J

PROVIDER: S-EPMC6008326 | biostudies-other | 2018 Jun

REPOSITORIES: biostudies-other

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18β-Glycyrrhetinic-acid-mediated unfolded protein response induces autophagy and apoptosis in hepatocellular carcinoma.

Chen Jin J Zhang Zhao-Qi ZQ Song Jia J Liu Qiu-Meng QM Wang Chao C Huang Zhao Z Chu Liang L Liang Hui-Fang HF Zhang Bi-Xiang BX Chen Xiao-Ping XP

Scientific reports 20180619 1

18β-Glycyrrhetinic acid (GA) is the active ingredient of the traditional Chinese medicine, Glycyrrhrzae Radix et Rhizoma. Here, we explored the effects of GA on hepatocellular carcinoma (HCC) in vitro and in vivo and the underlying molecular mechanisms. We confirmed that GA suppressed proliferation of various HCC cell lines. Treatment of GA caused G0/G1 arrest, apoptosis and autophagy in HCC cells. GA-induced apoptosis and autophagy were mainly due to the unfolded protein response. We compared t ...[more]

PMID: 29921924

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Project description:Platycodin D, the main saponin isolated from Chinese herb Platycodonis Radix, exhibits anticancer activities against various cancer cell lines. Here we evaluated its anticancer action against human hepatocellular carcinoma cells in vitro and in vivo, and elucidated the relationship between platycodin D-induced apoptosis and autophagy.The viability of human hepatocellular carcinoma BEL-7402 cells was evaluated with MTT assay, and the apoptosis was examined using Annexin V/PI and Hoechst 33342 staining assays. Monodansylcadaverine (MDC) staining was used to label autophagic vacuoles. The proteins were detected using Western blot analysis. For studying its anticancer action in vivo, platycodin D (5 and 10 mg· kg(-1)·d(-1)) was intraperitoneally injected to BEL-7402-bearing mice for 21 days.Platycodin D (5-40 μmol/L) inhibited the cell proliferation in vitro with IC50 values of 37.70±3.99, 24.30±2.30 and 19.70±2.36 μmol/L at 24, 48 and 72 h, respectively. Platycodin D (5-20 μmol/L) dose-dependently increased BEL-7402 cell apoptosis, increased the Bax/Bcl-2 ratio and the levels of cleaved PARP and cleaved caspase-3, and decreased the level of Bcl-2. Furthermore, platycodin D (5-20 μmol/L) induced autophagy in BEL-7402 cells, as evidenced by formation of cytoplasmic vacuoles, increased amounts of LC3-II, and increased numbers of MDC-positive cells. Pretreatment with the autophagy inhibitor chloroquine (5 μmol/L) or BAF (50 nmol/L) significantly enhanced platycodin D-induced proliferation inhibition and apoptosis. Moreover, platycodin D (20 μmol/L) activated the ERK and JNK pathways in BEL-7402 cells, and simultaneous blockage of the two pathways effectively suppressed platycodin D-induced autophagy and enhanced platycodin D-induced apoptosis. In BEL-7402-bearing mice, platycodin D (10 mg·kg(-1)•d(-1)) significantly reduced relative tumor volume with decreased body weight.Platycodin D not only inhibits the proliferation of BEL-7402 cells but also suppresses BEL-7402 xenograft tumor growth. Platycodin D-induced cell proliferation inhibition and apoptosis are amplified by co-treatment with autophagy inhibitors.

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18?-Glycyrrhetinic-acid-mediated unfolded protein response induces autophagy and apoptosis in hepatocellular carcinoma.

Publications

18β-Glycyrrhetinic-acid-mediated unfolded protein response induces autophagy and apoptosis in hepatocellular carcinoma.

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