Mifepristone inhibits hepatoma growth by enhancing the GR-HSP60-survivin interaction to facilitate survivin degradation

Ya-Hui Huang; Kwang-Huei Lin; Ming-Wei Lai; Chau-Ting Yeh

doi:10.7150/jca.86611

Mifepristone inhibits hepatoma growth by enhancing the GR-HSP60-survivin interaction to facilitate survivin degradation

J Cancer. 2023 Sep 18;14(16):3066-3077. doi: 10.7150/jca.86611. eCollection 2023.

Authors

Ya-Hui Huang^{1

2}, Kwang-Huei Lin^{1

3

4}, Ming-Wei Lai^{1

5}, Chau-Ting Yeh^{1

3

2}

Affiliations

¹ Liver Research Center, Chang Gung Memorial Hospital, Linkou Main Branch, Taoyuan, Taiwan.
² Molecular Medicine Research Center, Chang-Gung University, Taoyuan, Taiwan.
³ Department of Biochemistry, College of Medicine, Chang-Gung University, Taoyuan, Taiwan.
⁴ Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan.
⁵ Division of Pediatric Gastroenterology, Department of Pediatrics, Chang Gung Memorial Hospital Linkou Main Branch, Taoyuan, Taiwan.

Abstract

Silencing of heat shock protein 60 (HSP60) suppresses the growth of hepatocellular carcinoma (HCC). Mifepristone inhibits HSP60 mRNA expression in Chlamydophila-infected epithelial cells. The aim of this study was to determine whether mifepristone could inhibit the growth of HCC cells by affecting the functions of HSP60. The effect of mifepristone on cell viability was examined by flow cytometry and a cell proliferation assay. Protein-protein interactions were examined using the immunoprecipitation assay. The anti-tumor effect of mifepristone was evaluated using a xenograft model. Our results indicated that mifepristone induces cell cycle arrest at the G1 phase and early-stage apoptosis in HCC cells. Instead of reducing the total amount of HSP60, mifepristone induced the release of mitochondrial HSP60 into the cytosol by causing a loss of ΔΨm, thereby enhancing glucocorticoid receptor (GR)-HSP60-survivin complex formation as well as survivin degradation. Animal models have confirmed the growth inhibitory effects of mifepristone on HCC, including changes in the abundance of HSP60 in mitochondria and cytosol, decreased survivin and Ki-67-positive cells, as well as increased cell apoptosis. In conclusion, the inhibition of HCC growth by mifepristone may be achieved by altering the subcellular distribution of HSP60 to enhance the formation of cytosolic GR-HSP60-survivin complexes in the cells, leading to the degradation of survivin.

Keywords: HSP60; glucocorticoid receptor; hepatocellular carcinoma; mifepristone; survivin.