FMNL2/SRC-mediated androgen receptor translocation into the nucleus promotes enzalutamide resistance of prostate cancer

IF 4.6 2区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

iScience Pub Date : 2025-03-12 DOI:10.1016/j.isci.2025.112205

Jianpeng Yu , Yukui Gao , Mingpeng Zhang , Yue Gao , Chun Wang , Yuanjie Niu , Zhiqun Shang

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Abstract

Enzalutamide, a second-generation androgen receptor (AR) antagonist, has represented the association with improved overall survival in men with prostate cancer (PCa). However, PCa patients receiving enzalutamide will eventually develop resistance through various mechanisms without effective regimens. Here, we observed a higher level of formin-like 2 (FMNL2) in enzalutamide-resistant PCa cells. Functionally, FMNL2 knockdown partially re-sensitized enzalutamide-resistant PCa cells. Mechanistically, FMNL2 directly interacted with SRC kinase through FMNL2-FH1 and SRC-SH3 domain, which induced AR translocation from the cytoplasm to the nucleus, resulting in increased expression of the AR-targeted genes and leading to resistance to enzalutamide. Consistently, SRC inhibitor dasatinib rescued enzalutamide sensitivity and inhibited the proliferation of enzalutamide-resistant cancer cells. Taken together, our findings demonstrate a substantial role for FMNL2/SRC interaction in the regulation of AR translocation, suggesting that targeting FMNL2-mediated SRC activation might be a potential therapeutic strategy for enzalutamide-resistant PCa and dasatinib could be an option.

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来源期刊

iScience Multidisciplinary-Multidisciplinary

CiteScore

7.20

自引率

1.70%

发文量

1972

审稿时长

6 weeks

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