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Updated: Apr 7, 2026
Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Heat Shock Protein 90 Is a Potential Therapeutic Target in Cholangiocarcinoma
Tomoki Shirota1, Hidenori Ojima2, Nobuyoshi Hiraoka2
1Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan. Division of Surgery, Shinshu University School of Medicine, Nagano, Japan.
Abstract:
Cholangiocarcinoma is an aggressive malignancy with a poor prognosis, with no effective therapy other than surgical resection. Heat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in the posttranslational folding of a number of client proteins, many of which play essential roles in tumorigenesis. Here, we attempted to clarify its prognostic significance and potential utility as a therapeutic target in cholangiocarcinoma. Immunohistochemical expression of HSP90 was assessed retrospectively in 399 cholangiocarcinoma cases and 17 human cholangiocarcinoma cell lines, along with the effect of a small-molecule HSP90 inhibitor (NVP-AUY922) on cholangiocarcinoma tumor growth and angiogenesis in human cholangiocarcinoma cell lines and xenografts. The positivity of HSP90 was 44.6% in intrahepatic cholangiocarcinoma (IHCC) and 32.8% in extrahepatic cholangiocarcinoma (EHCC), respectively. HSP90 expression was significantly associated with the 5-year survival rate for IHCC (P < 0.001) and EHCC (P < 0.001). HSP90 inhibition showed potent antiproliferative activity and reduced growth-associated signaling in human cholangiocarcinoma cells in vitro. Furthermore, treatment of cholangiocarcinoma xenograft-bearing mice with NVP-AUY922 significantly inhibited growth at doses far below the maximum-tolerated dose. HSP90 overexpression is a prognostic marker for cholangiocarcinoma. HSP90-targeted therapy may be an option for a subset of cholangiocarcinoma.
Insights
Heat shock protein 90 (HSP90) overexpression indicates a poor prognosis in cholangiocarcinoma, a challenging cancer. Targeting HSP90 with inhibitors like NVP-AUY922 shows promise as a potential therapy for this aggressive malignancy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Cholangiocarcinoma (CCA) is an aggressive bile duct cancer with limited treatment options beyond surgery.
- Heat shock protein 90 (HSP90) is crucial for the stability and function of proteins involved in cancer cell growth and survival.
- The prognostic value and therapeutic potential of HSP90 in CCA remain to be fully elucidated.
Purpose of the Study:
- To investigate the prognostic significance of HSP90 expression in cholangiocarcinoma.
- To evaluate the efficacy of an HSP90 inhibitor as a potential therapeutic strategy for cholangiocarcinoma.
Main Methods:
- Immunohistochemical analysis of HSP90 expression in 399 cholangiocarcinoma patient samples and 17 cell lines.
- In vitro assessment of a small-molecule HSP90 inhibitor (NVP-AUY922) on cholangiocarcinoma cell proliferation and signaling.
- In vivo evaluation of NVP-AUY922 efficacy in cholangiocarcinoma xenograft mouse models.
Main Results:
- HSP90 positivity was observed in 44.6% of intrahepatic CCA and 32.8% of extrahepatic CCA cases.
- HSP90 expression significantly correlated with poorer 5-year survival rates in both IHCC and EHCC subtypes.
- NVP-AUY922 demonstrated potent anti-proliferative effects in vitro and significantly inhibited tumor growth in vivo with minimal toxicity.
Conclusions:
- Overexpression of HSP90 serves as a significant prognostic biomarker for cholangiocarcinoma.
- Targeting HSP90 with inhibitors represents a promising therapeutic avenue for a subset of cholangiocarcinoma patients.
