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Updated: May 3, 2026
Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
Targeting GRP75 improves HSP90 inhibitor efficacy by enhancing p53-mediated apoptosis in hepatocellular carcinoma
Weiwei Guo1, Lichong Yan1, Ling Yang1
1Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Abstract:
Heat shock protein 90 (HSP90) inhibitors are potential drugs for cancer therapy. The inhibition of HSP90 on cancer cell growth largely through degrading client proteins, like Akt and p53, therefore, triggering cancer cell apoptosis. Here, we show that the HSP90 inhibitor 17-AAG can induce the expression of GRP75, a member of heat shock protein 70 (HSP70) family, which, in turn, attenuates the anti-growth effect of HSP90 inhibition on cancer cells. Additionally, 17-AAG enhanced binding of GRP75 and p53, resulting in the retention of p53 in the cytoplasm. Blocking GRP75 with its inhibitor MKT-077 potentiated the anti-tumor effects of 17-AAG by disrupting the formation of GRP75-p53 complexes, thereby facilitating translocation of p53 into the nuclei and leading to the induction of apoptosis-related genes. Finally, dual inhibition of HSP90 and GRP75 was found to significantly inhibit tumor growth in a liver cancer xenograft model. In conclusion, the GRP75 inhibitor MKT-077 enhances 17-AAG-induced apoptosis in HCCs and increases p53-mediated inhibition of tumor growth in vivo. Dual targeting of GRP75 and HSP90 may be a useful strategy for the treatment of HCCs.
Insights
Heat shock protein 90 (HSP90) inhibitors like 17-AAG can be enhanced by blocking GRP75. Dual inhibition of HSP90 and GRP75 shows promise for treating liver cancer by promoting apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Heat shock protein 90 (HSP90) inhibitors are investigated for cancer therapy, primarily by degrading client proteins like Akt and p53 to induce apoptosis.
- HSP90 inhibition's anti-cancer effects can be modulated by other heat shock proteins.
Purpose of the Study:
- To investigate the role of GRP75 in mediating resistance to HSP90 inhibition in cancer cells.
- To evaluate the efficacy of dual inhibition of HSP90 and GRP75 as a therapeutic strategy for hepatocellular carcinoma (HCC).
Main Methods:
- Treatment of cancer cells with HSP90 inhibitor 17-AAG and GRP75 inhibitor MKT-077.
- Analysis of p53 localization and apoptosis-related gene expression.
- Assessment of tumor growth in a liver cancer xenograft model.
Main Results:
- 17-AAG treatment induced GRP75 expression, which attenuated the anti-growth effects of HSP90 inhibition.
- 17-AAG enhanced GRP75-p53 binding, leading to cytoplasmic retention of p53.
- Blocking GRP75 with MKT-077 potentiated 17-AAG's anti-tumor effects by promoting p53 nuclear translocation and apoptosis induction.
- Dual inhibition of HSP90 and GRP75 significantly inhibited tumor growth in vivo.
Conclusions:
- GRP75 inhibition enhances 17-AAG-induced apoptosis in HCC.
- Dual targeting of GRP75 and HSP90 represents a potential therapeutic strategy for HCC treatment.
