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Wogonoside promotes apoptosis and ER stress in human gastric cancer cells by regulating the IRE1? pathway.

ABSTRACT: Gastric cancer is a disease that occurs in the digestive system of humans and remains a problem in the medical field. Wogonoside, a natural flavonoid, has been reported to exert antitumor effects on various types of tumors. However, the effects of wogonoside on gastric cancer remain elusive. The aim of the present study was to detect whether wogonoside treatment could induce apoptosis and ER stress in gastric cancer cells. In the present study, CCK-8 assay was used to detect the cell viability, Annexin V/PI staining was used to detect the cells apoptosis, western blot analysis and real-time PCR analysis was used to detect the endoplasmic reticulum (ER) stress in the AGS and MKN-45 gastric cancer cell lines. Wogonoside treatment reduced the viability of AGS and MKN-45 cells and induced apoptosis. Furthermore, the expression level of caspase-3 and -9 significantly increased following wogonoside treatment compared with that in non-treated cells, and the protein expression levels of proapoptotic Bax and antiapoptotic Bcl-2 increased and decreased, respectively compared with that in the control group. In addition, the phosphorylated protein expression levels of mitogen-activated protein kinase kinase 5 (ASK1) and JNK increased following wogonoside treatment, and the protein expression levels of tumor necrosis factor receptor-associated factor 2 (TRAF2) and serine/threonine-protein kinase/endoribonuclease IRE1 (IRE1?) were also increased following treatment with 50 µM wogonoside for 48 h. Furthermore, the interactions between IRE1?, TRAF2 and ASK1 significantly increased following wogonoside treatment, suggesting that wogonoside induced endoplasmic reticulum (ER) stress in the AGS and MKN-45 cell lines. In addition, small interfering RNA-mediated silencing of IRE1? suppressed the activity of the IRE1?-TRAF2-ASK1 complex and prevented wogonoside-induced cell apoptosis. In conclusion, the results of the present study suggested that wogonoside exhibited antitumor activity by inducing ER stress-associated cell death through the IRE1?-TRAF2-ASK1 pathway.

SUBMITTER: Gu Q

PROVIDER: S-EPMC7938446 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Wogonoside promotes apoptosis and ER stress in human gastric cancer cells by regulating the IRE1α pathway.

Gu Qian Q Zhu Canhong C Wu Xi X Peng Lianghuan L Huang Genya G Hu Rong R

Experimental and therapeutic medicine 20210225 4

Gastric cancer is a disease that occurs in the digestive system of humans and remains a problem in the medical field. Wogonoside, a natural flavonoid, has been reported to exert antitumor effects on various types of tumors. However, the effects of wogonoside on gastric cancer remain elusive. The aim of the present study was to detect whether wogonoside treatment could induce apoptosis and ER stress in gastric cancer cells. In the present study, CCK-8 assay was used to detect the cell viability, ...[more]

PMID: 33692842

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Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed over 6 million individuals worldwide and continues to spread in countries where vaccines are not yet widely available, or its citizens are hesitant to become vaccinated. Therefore, it is critical to unravel the molecular mechanisms that allow SARS-CoV-2 and other coronaviruses to infect and overtake the host machinery of human cells. Coronavirus replication triggers endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), a key host cell pathway widely believed essential for viral replication. We examined the master UPR sensor IRE1α kinase/RNase and its downstream transcription factor effector XBP1s, which is processed through an IRE1α-mediated mRNA splicing event, in human lung-derived cells infected with betacoronaviruses. We found human respiratory coronavirus OC43 (HCoV-OC43), Middle East respiratory syndrome coronavirus (MERS-CoV), and murine coronavirus (MHV) all induce ER stress and strongly trigger the kinase and RNase activities of IRE1α as well as XBP1 splicing. In contrast, SARS-CoV-2 only partially activates IRE1α through autophosphorylation, but its RNase activity fails to splice XBP1. Moreover, while IRE1α was dispensable for replication in human cells for all coronaviruses tested, it was required for maximal expression of genes associated with several key cellular functions, including the interferon signaling pathway, during SARS-CoV-2 infection. Our data suggest that SARS-CoV-2 actively inhibits the RNase of autophosphorylated IRE1α, perhaps as a strategy to eliminate detection by the host immune system.ImportanceSARS-CoV-2 is the third lethal respiratory coronavirus after MERS-CoV and SARS-CoV to emerge this century, causing millions of deaths world-wide. Other common coronaviruses such as HCoV-OC43 cause less severe respiratory disease. Thus, it is imperative to understand the similarities and differences among these viruses in how each interacts with host cells. We focused here on the inositol-requiring enzyme 1α (IRE1α) pathway, part of the host unfolded protein response to virus-induced stress. We found that while MERS-CoV and HCoV-OC43 fully activate the IRE1α kinase and RNase activities, SARS-CoV-2 only partially activates IRE1α, promoting its kinase activity but not RNase activity. Based on IRE1α-dependent gene expression changes during infection, we propose that SARS-CoV-2 prevents IRE1α RNase activation as a strategy to limit detection by the host immune system.

Dataset Information

Wogonoside promotes apoptosis and ER stress in human gastric cancer cells by regulating the IRE1? pathway.

Publications

Wogonoside promotes apoptosis and ER stress in human gastric cancer cells by regulating the IRE1α pathway.

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