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Inhibition of USP14 Enhances the Sensitivity of Breast Cancer to Enzalutamide

Inhibition of USP14 Enhances the Sensitivity of Breast Cancer to Enzalutamide

Xiaohong Xia, Chuyi Huang, Yuning Liao, Yuan Liu, Jinchan He, Zhiqiang Guo, Lili Jiang, Xuejun Wang, Jinbao Liu, Hongbiao Huang

J Exp Clin Cancer Res. 2019 May 24;38(1):220.

PMID: 31126320

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP314245335	IU1		314245-33-5	Price
IAR42410930	USP14 Inhibitor, IU1			Price

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