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Role of Hsp-70 in triptolide-mediated cell death of neuroblastoma
Mara B Antonoff1, Rohit Chugh, Steven J Skube
1Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA. antonoff@umn.edu
Background:
Our recent work demonstrated that treatment of neuroblastoma with triptolide causes apoptotic cell death in vitro and decreases tumor size in vivo. Triptolide therapy has been associated with reduced expression of Hsp-70, suggesting a mechanism of cell killing involving Hsp-70 inhibition. The principal objective of this study was to investigate the role of Hsp-70 in triptolide-mediated cell death in neuroblastoma.
Materials And Methods:
Neuroblastoma cells were transfected with Hsp-70-specific siRNA. Viability, caspase activity, and phosphatidylserine externalization were subsequently measured. An orthotopic, syngeneic murine tumor model was developed, and randomized mice received daily injections of triptolide or vehicle. At 21 d, mice were sacrificed. Immunohistochemisty was used to characterize Hsp-70 levels in residual tumors, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed to identify cells undergoing apoptosis.
Results:
Targeted silencing of Hsp-70 with siRNA significantly decreased cellular viability, augmented caspase-3 activity, and resulted in increased annexin-V staining. These effects parallel those findings obtained following treatment with triptolide. Residual tumors from triptolide-treated mice showed minimal staining with Hsp-70 immunohistochemistry, while control tumors stained prominently. Tumors from treated mice demonstrated marked staining with the TUNEL assay, while control tumors showed no evidence of apoptosis.
Conclusions:
Use of siRNA to suppress Hsp-70 expression in neuroblastoma resulted in apoptotic cell death, similar to the effects of triptolide. Residual tumors from triptolide-treated mice expressed decreased levels of Hsp-70 and demonstrated significant apoptosis. These findings support the hypothesis that Hsp-70 inhibition plays a significant role in triptolide-mediated neuroblastoma cell death.
Insights
Triptolide treatment induces neuroblastoma cell death by inhibiting Heat Shock Protein 70 (Hsp-70). Silencing Hsp-70 mimics triptolide's effects, confirming its role in apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Triptolide induces neuroblastoma cell death and reduces tumor size.
- Triptolide therapy is linked to decreased Heat Shock Protein 70 (Hsp-70) expression.
- Hsp-70 inhibition is a potential mechanism for triptolide's anti-cancer effects.
Purpose of the Study:
- To investigate the role of Hsp-70 in triptolide-mediated neuroblastoma cell death.
- To determine if Hsp-70 inhibition is essential for triptolide's efficacy.
Main Methods:
- Neuroblastoma cells were treated with Hsp-70-specific siRNA.
- Cell viability, caspase activity, and phosphatidylserine externalization were measured.
- An orthotopic murine neuroblastoma model was used to assess triptolide's in vivo effects.
Main Results:
- Hsp-70 silencing decreased cell viability and increased apoptosis markers.
- Triptolide treatment significantly reduced Hsp-70 levels in tumors.
- Triptolide-treated tumors showed increased apoptosis via TUNEL assay.
Conclusions:
- Suppression of Hsp-70 induces apoptotic cell death in neuroblastoma.
- Triptolide treatment leads to decreased Hsp-70 expression and increased apoptosis.
- Hsp-70 inhibition is a key mechanism in triptolide-induced neuroblastoma cell death.
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