Inhibition of HSP90 exerts anti-tumor effect on angiosarcoma: Involvement of VEGF signaling pathway

Summary

Background

Angiosarcoma is a rare malignant neoplasm derived from endothelial cells and its prognosis is poor because advanced angiosarcoma is resistant to standard chemotherapy, and new therapies are urgently needed. Heat shock protein 90 (HSP90) has been identified as a molecular chaperone that regulates various cancer-related proteins. Numerous clinical trials are testing the effectiveness of HSP90 inhibitors in various types of malignancies.

Objectives

To investigate the role of HSP90 in the pathogenesis of angiosarcoma and whether inhibition of HSP90 may have anti-tumor activity.

Methods

The expression of HSP90 protein in angiosarcoma was examined with immunohistochemistry and immunoblotting. Effects of HSP90 inhibition were proven using proliferation, migration, and invasion assay in angiosarcoma cells. The mechanism of anti-tumor effect by HSP90 inhibition was investigated by the transfection of small interfering RNA (siRNA).

Results

The levels of HSP90 protein expression in cultured angiosarcoma cell lines were markedly increased compared to those in normal tissue cell lines. Immunohistochemical analyses revealed that the expression of HSP90 protein was strongly detected in angiosarcoma tissues compared with that in normal dermal vessels, or senile angioma tissues. Ganetespib, an HSP90 inhibitor, with or without taxanes, inhibited the proliferation of angiosarcoma cells via apoptosis in a dose-dependent manner. HSP90 siRNA suppressed the proliferation, migration, and invasion of angiosarcoma cells. Knockdown of HSP90 suppressed not directly vascular endothelial growth factor receptor 2 (VEGFR2) but selectively several downstream targets of vascular endothelial growth factor (VEGF) signaling in angiosarcoma cells.

Conclusions

HSP90 could be a novel therapeutic target for angiosarcoma.

This article is protected by copyright. All rights reserved.

http://ift.tt/2jGKoUC