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

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

doi:10.7150/jca.86611

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J Cancer 2023; 14(16):3066-3077. doi:10.7150/jca.86611 This issue Cite

Research Paper

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

Ya-Hui Huang^1,5✉ǂ, Kwang-Huei Lin^1,2,3ǂ, Ming-Wei Lai^1,4, Chau-Ting Yeh^1,2,5✉

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

Citation:

Huang YH, Lin KH, Lai MW, Yeh CT. Mifepristone inhibits hepatoma growth by enhancing the GR-HSP60-survivin interaction to facilitate survivin degradation. J Cancer 2023; 14(16):3066-3077. doi:10.7150/jca.86611. https://www.jcancer.org/v14p3066.htm

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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: mifepristone, HSP60, survivin, glucocorticoid receptor, hepatocellular carcinoma

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APA

Huang, Y.H., Lin, K.H., Lai, M.W., Yeh, C.T. (2023). Mifepristone inhibits hepatoma growth by enhancing the GR-HSP60-survivin interaction to facilitate survivin degradation. Journal of Cancer, 14(16), 3066-3077. https://doi.org/10.7150/jca.86611.

ACS

Huang, Y.H.; Lin, K.H.; Lai, M.W.; Yeh, C.T. Mifepristone inhibits hepatoma growth by enhancing the GR-HSP60-survivin interaction to facilitate survivin degradation. J. Cancer 2023, 14 (16), 3066-3077. DOI: 10.7150/jca.86611.

NLM

CSE

Huang YH, Lin KH, Lai MW, Yeh CT. 2023. Mifepristone inhibits hepatoma growth by enhancing the GR-HSP60-survivin interaction to facilitate survivin degradation. J Cancer. 14(16):3066-3077.

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