Celastrol impairs tumor growth by modulating the CIP2A-GSK3β-MCL-1 axis in gastric cancer cells
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1Department of Oncology, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, Hubei, China.
Background/Aim:
High Cancerous Inhibitor of PP2A (CIP2A) expression has been reported in solid and hematologic malignancies and is inversely associated with prognosis in Gastric Cancer, the non-small cell lung cancer, et al. CIP2A can be a drug target for the development of novel anti-gastric cancer agent. Our study was designed to explore the anti-cancer effect of celastrol, a small natural compound, and whether it has an anti-proliferative effect through inducing CIP2A degradation against gastric cancer cells.
Materials And Methods:
Employing human gastric cancer cells AGS and BCG-823 cells, the effects of celastrol on cell proliferation, apoptosis and cell cycle was specifically investigated via Annexin V-FITC/PI staining and CCK8 assay. The functional association between celastrol and CIP2A was evaluated by using CIP2A knockdown and overexpression technique. The mechanism of underlying celastrol-triggering anti-gastric cancer effect was detected by real-time PCR and western blot analysis.
Results:
Celastrol concentration- and time-dependently induced CIP2A degradation and led to gastric cancer cell apoptosis. More in depth studies revealed specific activation of Protein phosphatase 2A (PP2A)-GSK3β-MCL-1 signaling pathway was involved in pro-apoptosis effect of celastrol, due to celastrol-triggering degradation of CIP2A, which mainly suppressed PP2A activity.
Conclusion:
Our findings highlight that celastrol has therapeutic potential via inducing apoptosis of gastric cancer cells.
Insights
Celastrol induces cancerous inhibitor of PP2A (CIP2A) degradation, leading to gastric cancer cell apoptosis. This natural compound shows therapeutic potential against gastric cancer by activating the PP2A-GSK3β-MCL-1 pathway.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- High Cancerous Inhibitor of PP2A (CIP2A) expression is linked to poor prognosis in various cancers, including gastric cancer.
- CIP2A is a potential drug target for developing novel anti-gastric cancer therapies.
Purpose of the Study:
- To investigate the anti-cancer effects of celastrol on gastric cancer cells.
- To determine if celastrol induces apoptosis by promoting CIP2A degradation.
Main Methods:
- Utilized human gastric cancer cell lines (AGS, BCG-823).
- Assessed cell proliferation, apoptosis, and cell cycle using CCK8 assay and Annexin V-FITC/PI staining.
- Investigated the role of CIP2A via knockdown and overexpression.
- Analyzed signaling pathways using real-time PCR and western blot.
Main Results:
- Celastrol dose- and time-dependently reduced CIP2A levels, inducing gastric cancer cell apoptosis.
- Celastrol activated the Protein phosphatase 2A (PP2A)-GSK3β-MCL-1 signaling pathway.
- Celastrol-induced CIP2A degradation suppressed PP2A activity, contributing to apoptosis.
Conclusions:
- Celastrol demonstrates therapeutic potential for gastric cancer by inducing apoptosis.
- Targeting CIP2A degradation with celastrol offers a promising strategy for gastric cancer treatment.
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