Blocking autophagy enhances the apoptotic effect of 18β-glycyrrhetinic acid on human sarcoma cells via endoplasmic reticulum stress and JNK activation

Shen, Shuying; Zhou, Menglu; Huang, Kai; Wu, Yizheng; Ma, Yan; Wang, Jiying; Ma, Jianjun; Fan, Shunwu

doi:10.1038/cddis.2017.441

Cited by 30 publications

(27 citation statements)

References 44 publications

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“…Existing evidence demonstrated that ER stress plays a vital role in the induction of apoptosis and autophagy in various tumor cells, including melanoma cells [31], sarcoma cells [32], glioblastoma cells, gastric cancer cells [38], and liver cancer cells [39]. In this study, we found that XAG treatment induced apoptosis and ER stress mediated autophagy in Bel 7402 and SMMC 7721 cells.…”

Section: Discussionsupporting

confidence: 55%

“…A more recent evidence emphasized that JNK/c-jun pathway was involved in ER stress-mediated autophagy [32]. Thus, we attempted to investigate whether XAG-induced ER stress mediating autophagy through activation of JNK pathway.…”

Section: Resultsmentioning

confidence: 99%

“…Autophagy could enhance or abrogate apoptotic effect induced by prospective anti-cancer drugs in cancer cells [36]. Sheng et al demonstrated that isovitexin induced cytotoxic autophagy in liver cancer cells, and blocking autophagy abrogated the pro-apoptotic effect of isovitexin [32]. Similarly, studies conducted by Liu et al and Cheng et al also revealed that autophagy enhanced apoptotic cell death in ovarian cancer and glioblastoma cells, respectively [29].…”

Section: Discussionmentioning

confidence: 99%

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RETRACTED ARTICLE: Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma

Zhang

Gao

et al. 2019

J Exp Clin Cancer Res

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BackgroundXanthoangelol (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.MethodsThe 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.ResultsMechanistically, 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.ConclusionsCollectively, these results suggested that XAG could be served as a promising candidate for the treatment and prevention of HCC.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-1012-z) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 55%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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RETRACTED ARTICLE: Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma

Zhang

Gao

et al. 2019

J Exp Clin Cancer Res

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“…It is reported that the induction of ER stress by chemotherapeutic drug could further promote cell death by various mechanisms in cancer cells [17,18]. Considering that ER stress plays a crucial role in the regulation of cell death, as well as programmed necrosis [19,20], we speculated that PRIS might induce ER stress-mediated cell death in lung cancer.…”

Section: Introductionmentioning

confidence: 96%

Pristimerin Exacerbates Cellular Injury in Conditionally Reprogrammed Patient-Derived Lung Adenocarcinoma Cells by Aggravating Mitochondrial Impairment and Endoplasmic Reticulum Stress through EphB4/CDC42/N-WASP Signaling

Tang

Lei

Huang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Lung cancer is the most common and lethal malignant disease for which the development of efficacious chemotherapeutic agents remains an urgent need. Pristimerin (PRIS), a natural bioactive component isolated from various plant species in the Celastraceae and Hippocrateaceae families, has been reported to exhibit outstanding antitumor effects in several types of cells. However, the underlying mechanisms involved remain poorly understood. Here, we reported the novel finding that PRIS significantly suppressed lung cancer growth in conditionally reprogrammed patient-derived lung adenocarcinoma cells (CRLCs). We demonstrated that PRIS inhibited the cell viabilities, migrative and invaded abilities, and capillary structure formation of CRLCs. Furthermore, our results clarified that PRIS induced mitochondrial dysfunction through reactive oxygen species (ROS) generation, activation of caspase-9, caspase-3, and caspase-4, and expression of endoplasmic reticulum (ER) stress-associated proteins. Inhibition of ER stress by 4-PBA (4-phenylbutyric acid, a specific ER stress inhibitor) or CHOP siRNA transfection ameliorated PRIS-induced loss of mitochondrial membrane potential and intrinsic apoptosis. The present study also provides mechanistic evidence that PRIS suppressed the EphB4/CDC42/N-WASP signaling pathway, which is required for mitochondrial-mediated intrinsic apoptosis, activation of ER stress, and stimulation of caspase-4 induced by PRIS, and consequently resulting in suppressed cell viability, migration, and angiogenesis in CRLCs. Taken together, by providing a mechanistic insight into the modulation of ER stress-induced cell death in CRLCs by PRIS, we suggest that PRIS has a strong potential of being a new antitumor therapeutic agent with applications in the fields of human lung adenocarcinoma.

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“…Accumulating evidence suggests that autophagy can both suppress and promote tumor functions in cancer progression [6,7]. On the one hand, the initial stages of tumorigenesis can be inhibited by autophagy [8] and on the other, autophagy could nurture established cancers [9][10][11]. Yang et al [12] revealed the mechanism of how autophagy promotes pancreatic tumor growth via p53 alternation.…”

Section: Introductionmentioning

confidence: 99%

Combination of interferon-gamma and autophagy inhibitor as a therapeutic approach in oral squamous cell carcinoma

Zhou¹,

Zhao²,

Liang³

et al. 2020

Preprint

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Background: Former clinical trials and experimental research have indicated that interferon-gamma (IFNγ) therapy does not achieve an ideal effect in solid tumors. Autophagy has been associated with tumor chemoresistance. The aim of this study was to explore the efficacy of IFNγ and autophagy inhibitor in the combination treatment of oral squamous cell carcinoma (OSCC). Method: IFNγ-induced apoptosis was evaluated by the expression of relative proteins (cleaved-PARP and caspase-3) and flow cytometry. IFNγ-induced autophagy was assessed by the expression of Beclin1, LC3B, and P62. The synergistic effect of IFNγ and autophagy inhibitor (chloroquine) was evaluated in vitro and in vivo.Findings: IFNγ induced anti-proliferation, apoptosis, and autophagy in OSCC cells. Autophagy-related protein 5 (ATG5) was a key feature in IFNγ-induced autophagy flux. IFNγ and chloroquine had obvious synergistic effects on cellular growth inhibition and apoptosis promotion in OSCC cells and xenograft models. Interpretation: Our findings suggest that IFNγ-induced autophagy plays a cellular protective role, and blocking autophagy flux can promote IFNγ-mediated OSCC cell apoptosis. The combination of IFNγ and autophagy inhibitors represents a novel strategy for OSCC therapy.

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Blocking autophagy enhances the apoptotic effect of 18β-glycyrrhetinic acid on human sarcoma cells via endoplasmic reticulum stress and JNK activation

Cited by 30 publications

References 44 publications

RETRACTED ARTICLE: Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma

RETRACTED ARTICLE: Endoplasmic reticulum stress triggers Xanthoangelol-induced protective autophagy via activation of JNK/c-Jun Axis in hepatocellular carcinoma

Pristimerin Exacerbates Cellular Injury in Conditionally Reprogrammed Patient-Derived Lung Adenocarcinoma Cells by Aggravating Mitochondrial Impairment and Endoplasmic Reticulum Stress through EphB4/CDC42/N-WASP Signaling

Combination of interferon-gamma and autophagy inhibitor as a therapeutic approach in oral squamous cell carcinoma

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