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Endoplasmic reticulum stress activation mediates Ginseng Rg3-induced anti-gallbladder cancer cell activity
Keren Wu1, Ning Li1, Huaqin Sun2
1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China.
Abstract:
In the current study, we examined the potential effect of Ginsenoside Rg3 against gallbladder cancer cells, the underlying signaling mechanisms were also studied. We demonstrated that Rg3 exerted potent cytotoxic and pro-apoptotic activity against established and primary human gallbladder cancer cells. Yet it was safe to non-cancerous gallbladder epithelial cells. At the molecular level, we showed that Rg3 induced endoplasmic reticulum (ER) stress activation, the latter was evidenced by C/EBP homologous protein (CHOP) upregulation, inositol-requiring enzyme 1 (IRE1)/PKR-like endoplasmic reticulum kinase (PERK) phosphorylations, and caspase-12 activation in gallbladder cancer cells. Reversely, the ER stress inhibitor salubrinal, the caspase-12 inhibitor z-ATAD-fmk as well as CHOP shRNA knockdown significantly attenuated Rg3-induced cytotoxicity against gallbladder cancer cells. In vivo, we showed that Rg3 oral administration significantly inhibited GBC-SD gallbladder cancer xenograft growth in nude mice, its activity was, however, compromised with co-administration of the ER stress inhibitor salubrinal. Thus, we suggest that ER stress activation mediates Ginseng Rg3-induced anti-gallbladder cancer cell activity in vitro and in vivo.
Insights
Ginsenoside Rg3 effectively kills gallbladder cancer cells by activating endoplasmic reticulum (ER) stress, while sparing normal cells. This ER stress pathway is crucial for Rg3
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Gallbladder cancer (GBC) remains a significant health challenge with limited effective treatments.
- Ginsenoside Rg3, a compound derived from ginseng, has shown potential anti-cancer properties.
- Understanding the precise mechanisms of Rg3's action is crucial for therapeutic development.
Purpose of the Study:
- To investigate the anti-cancer effects of Ginsenoside Rg3 on human gallbladder cancer cells.
- To elucidate the molecular signaling pathways involved in Rg3-mediated cancer cell death.
- To evaluate the efficacy of Rg3 in preclinical models of gallbladder cancer.
Main Methods:
- In vitro studies using established and primary human gallbladder cancer cell lines.
- Molecular analysis including Western blotting for protein expression and phosphorylation.
- In vivo studies using gallbladder cancer xenograft models in nude mice.
Main Results:
- Ginsenoside Rg3 demonstrated significant cytotoxic and pro-apoptotic effects specifically against gallbladder cancer cells, with no observed toxicity in normal gallbladder epithelial cells.
- Rg3 induced endoplasmic reticulum (ER) stress, evidenced by increased C/EBP homologous protein (CHOP) and phosphorylation of inositol-requiring enzyme 1 (IRE1)/PKR-like endoplasmic reticulum kinase (PERK), and caspase-12 activation.
- Inhibition of ER stress pathways (using salubrinal, z-ATAD-fmk, or CHOP knockdown) significantly reduced Rg3's cytotoxicity.
- Oral administration of Rg3 inhibited tumor growth in a gallbladder cancer xenograft model, an effect diminished by co-administration of the ER stress inhibitor salubrinal.
Conclusions:
- Endoplasmic reticulum (ER) stress activation is a key mechanism underlying the anti-gallbladder cancer activity of Ginsenoside Rg3.
- Ginsenoside Rg3 exhibits selective toxicity towards cancer cells and holds promise as a therapeutic agent for gallbladder cancer.
- Targeting ER stress pathways may enhance the efficacy of Ginsenoside Rg3 in treating gallbladder cancer.
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