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Sodium demethylcantharidate induces apoptosis in hepatocellular carcinoma cells via ER stress.

ABSTRACT: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, characterized by a high degree of malignancy, a poor prognosis, and chemotherapy resistance. The anticancer activities of cantharidin and its derivatives have been widely reported. Sodium demethylcantharidate is a derivative of cantharidin that shows excellent anticancer activity against multiple types of cancer, including HCC. However, its mechanism of action remains unclear. We evaluated the anticancer activities of sodium demethylcantharidate in SMMC-7721 and Bel-7402 HCC cells in the current study and demonstrated that sodium demethylcantharidate effectively inhibited the proliferation of SMMC-7721 and Bel-7402 HCC cells in a dose- and time-dependent manner. Flow cytometry analysis showed that sodium demethylcantharidate could induce apoptosis. Western blotting revealed that endoplasmic reticulum (ER) stress-related proteins (p-IRE1, GRP78/BiP, CHOP, the spliced form of XBP1, and caspase-12) were upregulated in SMMC-7721 and Bel-7402 cells after exposure to sodium demethylcantharidate. Based on those results, we confirmed that sodium demethylcantharidate could induce apoptosis via ER stress. Moreover, a significant attenuation of SMMC-7721 cell tumorigenesis was observed after sodium demethylcantharidate treatment in a nude mouse xenograft model. These findings elucidate one mechanism underlying the anticancer activity of sodium demethylcantharidate against HCC.

SUBMITTER: Ye M

PROVIDER: S-EPMC6556643 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Sodium demethylcantharidate induces apoptosis in hepatocellular carcinoma cells via ER stress.

Ye Meng M Zhu Xinting X Yan Rong R Hui Jing J Zhang Jianyong J Liu Yun Y Li Xiaofei X

American journal of translational research 20190515 5

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, characterized by a high degree of malignancy, a poor prognosis, and chemotherapy resistance. The anticancer activities of cantharidin and its derivatives have been widely reported. Sodium demethylcantharidate is a derivative of cantharidin that shows excellent anticancer activity against multiple types of cancer, including HCC. However, its mechanism of action remains unclear. We evaluated the anticancer activit ...[more]

PMID: 31217884

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Project description:BackgroundTrichomonas vaginalis causes lesions on the cervicovaginal mucosa in women; however, its pathogenesis remains unclear. We have investigated the involvement of the endoplasmic reticulum (ER) in the induction of apoptosis by T. vaginalis and its molecular mechanisms in human cervical cancer SiHa cells.MethodsApoptosis, reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP), ER stress response and Bcl-2 family protein expression were evaluated using immunocytochemistry, flow cytometry, 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine iodide dye staining and western blotting.ResultsTrichomonas vaginalis induced mitochondrial ROS production, apoptosis, the ER stress response and mitochondrial dysfunction, such as MMP depolarization and an imbalance in Bcl-2 family proteins, in SiHa cells in a parasite burden- and infection time-dependent manner. Pretreatment with N-acetyl cysteine (ROS scavenger) or 4-phenylbutyric acid (4-PBA; ER stress inhibitor) significantly alleviated apoptosis, mitochondrial ROS production, mitochondrial dysfunction and ER stress response in a dose-dependent manner. In addition, T. vaginalis induced the phosphorylation of apoptosis signal regulating kinase 1 (ASK1) and c-Jun N-terminal kinases (JNK) in SiHa cells, whereas 4-PBA or SP600125 (JNK inhibitor) pretreatment significantly attenuated ASK1/JNK phosphorylation, mitochondrial dysfunction, apoptosis and ER stress response in SiHa cells, in a dose-dependent manner. Furthermore, T. vaginalis excretory/secretory products also induced mitochondrial ROS production, apoptosis and the ER stress response in SiHa cells, in a time-dependent manner.ConclusionsTrichomonas vaginalis induces apoptosis through mitochondrial ROS and ER stress responses, and also promotes ER stress-mediated mitochondrial apoptosis via the IRE1/ASK1/JNK/Bcl-2 family protein pathways in SiHa cells. These data suggest that T. vaginalis-induced apoptosis is affected by ROS and ER stress response via ER-mitochondria crosstalk.

Project description:BackgroundMarchantia polymorpha L. is a kind of Chinese herbal medicine and has various biological activities including antioxidant and antifungal. However, it is not clear about the antitumor effect and mechanism of M. polymorpha. We prepared M. polymorpha ethanol extract (MPEE) and investigated its antitumor effect on hepatocellular carcinoma cells both in vitro and in vivo.MethodsThe viability of hepatocellular carcinoma cells was detected by MTT assay. The distribution of cell cycle was analyzed by propidium iodide (PI) staining. The morphology of nuclei was observed by Hoechst 33258 staining. Apoptosis was detected by Annexin V/PI staining. JC-1 fluorescent probe and DCFH-DA were used to detect the mitochondrial membrane potential (ΔψM) and the level of reactive oxygen species (ROS), respectively. Caspase inhibitors were used to test the function of caspase in the induction of apoptosis. Quantitative real time polymerase chain reaction (qRT-PCR) and Western blot were used to evaluate the levels of mRNA and protein, respectively. Differentially expressed genes and signaling pathways were identified by transcriptome analysis. The H22 tumor mouse model was used to detect the antitumor effect of the extract.ResultsMPEE significantly suppressed the migration and growth of BEL-7404, HepG2 and H22 cells in a dose- and time-dependent manner through induction of apoptosis characterized by chromosomal condensation and cell cycle arrest at G0/G1 and G2/M phases. MPEE induced mitochondria-dependent apoptosis via upregulation of Bax and downregulation of Bcl-2 to reduce mitochondrial membrane potential and increase the release of cytochrome c. The levels of cleaved caspase-8 and -9 were significantly increased, which sequentially activated caspase-3 to cleave PARP. We further found that MPEE significantly increased ROS production and activated endoplasmic reticulum (ER) stress associated-apoptotic signaling pathway. Moreover, MPEE significantly inhibited H22 tumor growth in mouse model and improved the survival of tumor mice.ConclusionThese results suggested that MPEE suppressed hepatocellular carcinoma cell growth through induction of apoptosis via intrinsic- and ER stress-associated pathways.

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Sodium demethylcantharidate induces apoptosis in hepatocellular carcinoma cells via ER stress.

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Sodium demethylcantharidate induces apoptosis in hepatocellular carcinoma cells via ER stress.

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