Inhibition of USP14 enhances the sensitivity of breast cancer to enzalutamide.

Abstract

BACKGROUND:

Androgen receptor (AR) is expressed in approximately 70% of breast tumors. Recent studies increasingly support AR as a potential therapeutic target of AR-positive breast cancer. We have previously reported that deubiquitinase USP14 stabilizes AR proteins by deubiquitination and USP14 inhibition results in inhibition of cell growth and tumor progression in AR-positive prostate cancer and breast cancer. The current study aims to explore the anticancer effect of a treatment combining AR antagonist enzalutamide with USP14 inhibition on breast cancer cells.

METHODS:

The combining effects of enzalutamide and USP14 inhibition on breast cancer cell proliferation and apoptosis and associated cell signaling were evaluated in vitro and in vivo.

RESULTS:

USP14 inhibition via administration of IU1 or USP14-specific siRNA/shRNA enhanced cell growth inhibition and apoptosis induction by enzalutamide in breast cancer cell lines in vitro and in vivo. Additionally, the combination of enzalutamide with USP14 inhibition/knockdown induced significant downregulation of AR proteins and suppression of AR-related signaling pathways, including Wnt/β-catenin and PI3K/AKT pathways. Moreover, AKT inhibition via MK2206 increased the antiproliferative and proapoptotic effects of enzalutamide+IU1 combined treatment.

CONCLUSION:

Collectively, our data suggest that USP14 inhibition in combination with enzalutamide represents a potentially new therapeutic strategy for breast cancer.

• Authors: Xiaohong Xia, Chuyi Huang, Yuning Liao, Yuan Liu, Jinchan He, Zhiqiang Guo, Lili Jiang, Xuejun Wang, Jinbao Liu, Hongbiao Huang
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 38 Issue 1 Pg. 220 (May 24 2019) ISSN: 1756-9966 [Electronic] England
• PMID: 31126320 (Publication Type: Journal Article)

Chemical References

• 1-(1-(4-fluorophenyl)-2,5-dimethylpyrrol-3-yl)-2-pyrrolidin-1-ylethanone
• Benzamides
• Heterocyclic Compounds, 3-Ring
• MK 2206
• Nitriles
• Pyrroles
• Pyrrolidines
• USP14 protein, human
• Phenylthiohydantoin
• enzalutamide
• Ubiquitin Thiolesterase

Topics

• Animals
• Benzamides
• Breast Neoplasms (drug therapy, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Down-Regulation
• Drug Resistance, Neoplasm (drug effects)
• Drug Synergism
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Heterocyclic Compounds, 3-Ring (administration & dosage, pharmacology)
• Humans
• MCF-7 Cells
• Mice
• Nitriles
• Phenylthiohydantoin (administration & dosage, analogs & derivatives, pharmacology)
• Pyrroles (administration & dosage, pharmacology)
• Pyrrolidines (administration & dosage, pharmacology)
• Signal Transduction (drug effects)
• Ubiquitin Thiolesterase (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays