恩扎鲁胺
前列腺癌
雄激素受体
癌症研究
生物
癌症
雄激素
雄激素剥夺疗法
内科学
内分泌学
医学
激素
作者
Joy C. Yang,Pengfei Xu,Shu Ning,Logan J. Wasielewski,Hans Adomat,Sung Hee Hwang,Christophe Morisseau,Martin Gleave,Eva Corey,Allen C. Gao,Primo N. Lara,Christopher P. Evans,Bruce D. Hammock,Chengfei Liu
出处
期刊:Oncogene
[Springer Nature]
日期:2023-01-03
卷期号:42 (9): 693-707
被引量:1
标识
DOI:10.1038/s41388-022-02566-6
摘要
Castration-resistant prostate cancer (CRPC) is the main driving force of mortality in prostate cancer patients. Among the parameters contributing to the progression of CRPC and treatment failure, elevation of the steroidogenic enzyme AKR1C3 and androgen receptor variant 7 (AR-V7) are frequently reported. The AKR1C3/AR-V7 complex has been recognized as a major driver for drug resistance in advanced prostate cancer. Herein we report that the level of AKR1C3 is reciprocally regulated by the full-length androgen receptor (AR-FL) through binding to the distal enhancer region of the AKR1C3 gene. A novel function of PTUPB in AKR1C3 inhibition was discovered and PTUPB showed more effectiveness than indomethacin and celecoxib in suppressing AKR1C3 activity and CRPC cell growth. PTUPB synergizes with enzalutamide treatment in tumor suppression and gene signature regulation. Combination treatments with PTUPB and enzalutamide provide benefits by blocking AR/AR-V7 signaling, which inhibits the growth of castration relapsed VCaP xenograft tumors and patient-derived xenograft organoids. Targeting of the ARK1C3/AR/AR-V7 axis with PTUPB and enzalutamide may overcome drug resistance to AR signaling inhibitors in advanced prostate cancer.
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