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Heat Shock Protein 60 (HSP60) Serves as a Potential Target for the Sensitization of Chemoresistant Ovarian Cancer Cells

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Abstract

HSP60 is a mitochondrial chaperone protein that is associated with decreased overall survival of ovarian cancer patients. We determined whether targeting HSP60 with its monoclonal antibody would induce cytotoxicity in sensitive and chemoresistant ovarian cancer cells and whether it is synergistic when combined with chemotherapeutic drugs. Epithelial ovarian cancer (EOC) cells and their docetaxel- or cisplatin-resistant counterparts were utilized. HSP60 mRNA levels were determined by real-time RT-PCR. Cytotoxicity of HSP60 antibody (0.5 or 1.5 μg/ml) alone and in combination with chemotherapy were assessed by MTT Cell Proliferation Assay. Unpaired t tests were used to compare groups for real-time RT-PCR. One-way ANOVA followed by Tukey’s post hoc tests with Bonferroni correction was performed for cytotoxicity comparisons. Significant synergistic effects of the antibody combined with chemotherapy were determined by the CompuSyn Software. Basal HSP60 mRNA levels were increased in chemoresistant EOC cells as compared with their sensitive counterparts (p < 0.05). There was no significant difference in cytotoxicity between EOC cell types; however, treatment with the HSP60 antibody for 24 h showed a dose response (0.5 and 1.5 μg/ml) cytotoxic effect to both sensitive and chemoresistant EOC cells as compared with the isotype control (p < 0.05). Importantly, treatment with both doses of HSP60 antibody was not cytotoxic to normal macrophages. Combination of the HSP60 antibody with docetaxel or cisplatin was significantly synergistic in both sensitive and chemoresistant EOC cells. Here, we identify a novel target that may serve not only for ovarian cancer treatment but also for sensitization of patients to chemotherapy. The cytotoxic effect of HSP60 monoclonal antibody and its synergism with chemotherapeutic agents highlight HSP60 as a promising target for therapy and chemosensitization in ovarian cancer treatment.

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Authors and Affiliations

  1. Division of Gynecologic Oncology, Karmanos Cancer Institute, Detroit, MI, USA

    Amy K. Harper, Robert T. Morris & Ghassan M. Saed

  2. The C.S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA

    Nicole M. Fletcher, Rong Fan & Ghassan M. Saed

  3. Departments of Obstetrics and Gynecology and Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA

    Ghassan M. Saed

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  1. Amy K. Harper
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  2. Nicole M. Fletcher
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  3. Rong Fan
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Correspondence to Ghassan M. Saed.

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Highlights

1. Heat shock protein 60 (HSP60) is overexpressed in chemoresistant epithelial ovarian cancer (EOC).

2. Targeting EOC cells with HSP60 monoclonal antibody induces cytotoxicity.

3. Combining chemotherapy with HSP60 monoclonal antibody causes synergistic killing of EOC cells.

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Harper, A.K., Fletcher, N.M., Fan, R. et al. Heat Shock Protein 60 (HSP60) Serves as a Potential Target for the Sensitization of Chemoresistant Ovarian Cancer Cells. Reprod. Sci. 27, 1030–1036 (2020). https://doi.org/10.1007/s43032-019-00089-2

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  • DOI: https://doi.org/10.1007/s43032-019-00089-2

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