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Updated: Jul 8, 2026
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
A novel Hsp90 inhibitor to disrupt Hsp90/Cdc37 complex against pancreatic cancer cells
Tao Zhang1, Adel Hamza, Xianhua Cao
1Division of Pharmaceutics, College of Pharmacy, The Ohio State University, 500 West 12th Avenue, Columbus, OH 43210, USA.
Abstract:
Pancreatic cancer is an aggressive disease with multiple biochemical and genetic alterations. Thus, a single agent to hit one molecular target may not be sufficient to treat this disease. The purpose of this study is to identify a novel Hsp90 inhibitor to disrupt protein-protein interactions of Hsp90 and its cochaperones for down-regulating many oncogenes simultaneously against pancreatic cancer cells. Here, we reported that celastrol disrupted Hsp90-Cdc37 interaction in the superchaperone complex to exhibit antitumor activity in vitro and in vivo. Molecular docking and molecular dynamic simulations showed that celastrol blocked the critical interaction of Glu33 (Hsp90) and Arg167 (Cdc37). Immunoprecipitation confirmed that celastrol (10 micromol/L) disrupted the Hsp90-Cdc37 interaction in the pancreatic cancer cell line Panc-1. In contrast to classic Hsp90 inhibitor (geldanamycin), celastrol (0.1-100 micromol/L) did not interfere with ATP binding to Hsp90. However, celastrol (1-5 micromol/L) induced Hsp90 client protein degradation (Cdk4 and Akt) by 70% to 80% and increased Hsp70 expression by 12-fold. Celastrol induced apoptosis in vitro and significantly inhibited tumor growth in Panc-1 xenografts. Moreover, celastrol (3 mg/kg) effectively suppressed tumor metastasis by more than 80% in RIP1-Tag2 transgenic mouse model with pancreatic islet cell carcinogenesis. The data suggest that celastrol is a novel Hsp90 inhibitor to disrupt Hsp90-Cdc37 interaction against pancreatic cancer cells.
Insights
Celastrol, a novel Hsp90 inhibitor, disrupts Hsp90-Cdc37 interactions, showing antitumor and anti-metastasis effects against pancreatic cancer. This approach targets multiple oncogenes simultaneously for effective treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Pancreatic cancer is aggressive, driven by numerous genetic and biochemical alterations.
- Targeting a single molecular pathway may be insufficient for effective pancreatic cancer treatment.
Purpose of the Study:
- To identify a novel Heat Shock Protein 90 (Hsp90) inhibitor.
- To disrupt Hsp90-cochaperone interactions, down-regulating multiple oncogenes simultaneously in pancreatic cancer cells.
Main Methods:
- Molecular docking and dynamic simulations to predict binding interactions.
- Immunoprecipitation to confirm Hsp90-Cdc37 disruption in pancreatic cancer cells.
- In vitro and in vivo assays to evaluate antitumor and anti-metastasis efficacy.
Main Results:
- Celastrol blocked the critical interaction between Hsp90 (Glu33) and Cdc37 (Arg167).
- Celastrol disrupted Hsp90-Cdc37 interaction in Panc-1 cells without affecting ATP binding.
- Celastrol induced degradation of Hsp90 client proteins (Cdk4, Akt), increased Hsp70, promoted apoptosis, inhibited tumor growth, and suppressed metastasis.
Conclusions:
- Celastrol acts as a novel Hsp90 inhibitor by disrupting the Hsp90-Cdc37 interaction.
- Celastrol demonstrates significant antitumor and anti-metastasis potential against pancreatic cancer.
- This Hsp90 inhibitor offers a promising strategy for targeting multiple oncogenic pathways in pancreatic cancer.
