期刊
MOLECULAR CANCER THERAPEUTICS
卷 20, 期 2, 页码 398-409出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-20-0244
关键词
-
类别
资金
- William L. Bray and Joe C. Davis Foundation
- Vanderbilt Institute for Clinical and Translational Research (VICTR)
- National Center for Advancing Translational Sciences (NCATS) Clinical Translational Science Award (CTSA) Program [5UL1TR002243]
- Case Research Institute
- Cell and Molecular Biology Training Program [T32 GM 008056]
- Molecular Therapeutics Training Program [T32 GM 008803]
A short hairpin RNA screen identified 11 genes supporting enzalutamide resistance, with validation experiments confirming the roles of ACAT1, MAP3K11, and PSMD12 in vitro. Inhibition of MAP3K11 in combination with enzalutamide led to increased cell death, suggesting potential therapeutic strategies for castration-resistant prostate cancer.
Castration-resistant prostate cancer can be treated with the antiandrogen enzalutamide, but responses and duration of response arc variable. To identify genes that support enzalutamide resistance, we performed a short hairpin RNA (shRNA) screen in the bone-homing, castration-resistant prostate cancer cell line, C4-2B. We identified 11 genes (TFAP2C, CAD, SPDEF, EIF6, GABRG2, CDC37, PSMD12, COL5A2, AR, MAP3K11, and ACAT1) whose loss resulted in decreased cell survival in response to enzalutamide. To validate our screen, we performed transient knockdowns in CA-2B and 22Rv1 cells and evaluated cell survival in response to enzalutamide. Through these studies, we validated three genes (ACAT1, MAP3K11, and PSMD12) as supporters of enzalutamide resistance in vitro. Although ACAT1 expression is lower in metastatic castration-resistant prostate cancer samples versus primary prostate cancer samples, knockdown of ACAT1 was sufficient to reduce cell survival in C4-2B and 22Rv1 cells. MAP3K11 expression increases with Gleason grade, and the highest expression is observed in metastatic castration-resistant disease. Knockdown of MAP3K11 reduced cell survival, and pharmacologic inhibition of MAP3K11 with CEP-1347 in combination with enzalutamide resulted in a dramatic increase in cell death. This was associated with decreased phosphorylation of AR-Serine650, which is required for maximal AR activation. Finally, although PSMD12 expression did not change during disease progression, knockdown of PSMD12 resulted in decreased AR and AR splice variant expression, likely contributing to the C4-2B and 22Rv1 decrease in cell survival. Our study has therefore identified at least three new supporters of enzalutamide resistance in castration-resistant prostate cancer cells in vitro.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据