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

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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture, Prostate Gland Growth

DISEASE(S): Prostate Adenocarcinoma

SUBMITTER: Jianpeng Yu

LAB HEAD: zhiqun shang

PROVIDER: PXD059539 | Pride | 2025-01-13

REPOSITORIES: pride

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	P20190600948_F1.raw	Raw
	P20190600948_F10.raw	Raw
	P20190600948_F11.raw	Raw
	P20190600948_F12.raw	Raw
	P20190600948_F13.raw	Raw

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