The anti-cancer mechanism of Celastrol by targeting JAK2/STAT3 signaling pathway in gastric and ovarian cancer.
Toxicol Appl Pharmacol
; : 117077, 2024 Aug 22.
Article
in En
| MEDLINE
| ID: mdl-39181414
ABSTRACT
BACKGROUND:
Celastrol is a natural triterpene exhibiting significant and extensive antitumor activity in a wide range of cancer. Due to unfavorable toxicity profile and undefined mechanism, Celastrol's application in clinical cancer therapy remains limited. Herein, we elucidate the pharmacological mechanism of Celastrol's anticancer effects, with a fucus on STAT3 signaling pathway in cancers with high incidence of metastasis.METHODS:
The safety profile of Celastrol were assessed in mice. In vitro analysis was performed in gastric cancer and ovarian cancer to assess the cytotoxicity, induction of reactive oxygen species (ROS) of Celastrol using STAT3 knockout cancer cells. Effects of Celastrol on STAT3 activation and transcription activity, JAK2/STAT3 signaling protein expression were assessed. Additionally, proteomic contrastive analysis was performed to explore the molecular association of Celastrol with STAT3 deletion in cancer cells.RESULTS:
Celastrol has no obvious toxic effect at 1.5â¯mg/kg/day in a 1â¯5â¯days' administration. Celastrol inhibits tumor growth and increases ROS in a STAT3 dependent manner in gastric and ovarian cancer celllines. On molecular level, it downregulates IL-6 level and inhibits the JAK2/STAT3 signaling pathway by suppressing STAT3' activation and transcription activity. Proteomic contrastive analysis suggests a similar cellular mechanism of action between Celastrol and STAT3 deletion on regulating cancer progression pathways related to migration and invasion.CONCLUSION:
Our research elucidates the anti-cancer mechanism of Celastrol through targeting the JAK2/STAT3 signaling pathway in cancer with high incidence of metastasis. This study provides a solid theoretical basis for the application of Celastrol in cancer therapy.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Toxicol Appl Pharmacol
Year:
2024
Document type:
Article
Affiliation country:
China
Publication country:
EEUU
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ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
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UNITED STATES
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UNITED STATES OF AMERICA
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US
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USA