Abstract
BackgroundAndrogen receptor (AR) plays important role in the development, progression, and metastasis of prostate cancer (PCa). Caffeic acid phenethyl ester (CAPE) is the main component of honey bee propolis. We determined if CAPE affects the signaling and stability of AR in PCa cells.MethodsEffects of CAPE on AR transcriptional activity and localization were determined by reporter gene assay and immunofluorescent microscopy. Western blotting, fluorescent polarization, computer simulation, and animal experiment were performed to investigate the molecular mechanism how CAPE reduces the stability of AR.ResultsCAPE treatment dose-dependently suppressed the transcriptional activity of AR as well as the protein levels of AR and its target gene PSA. Cyclohexamide treatment revealed that androgen stabilized AR protein, but AR stability was diminished by CAPE. Fluorescence microscopy demonstrated that androgen promoted the nucleus translocation of AR in PCa cells, while treatment with CAPE reduced protein level of AR in both nucleus and cytoplasm. CAPE treatment suppressed the phosphorylation of Ser81 and Ser213 on AR, which regulates the stability of AR. CDK1 and AKT are the kinases phosphorylating Ser81 and Ser213 on AR, respectively. CAPE treatment significantly reduced the protein level and activity of CDK1 and AKT in PCa cells. Overexpression of CDK1 or AKT rescued the AR protein level under CAPE treatment.ConclusionsOur results suggested that CAPE treatment reduced AR stability and AR transcriptional activity in PCa cells, implying the possibility of using CAPE as a treatment for advanced PCa.Graphical abstract
Highlights
Androgen receptor (AR) plays important role in the development, progression, and metastasis of prostate cancer (PCa)
Caffeic acid phenethyl ester (CAPE) inhibits AR transcriptional activity To determine if CAPE treatment interferes AR transcriptional activity, we expressed AR in human embryonic kidney (HEK) 293 cells, which is AR-negative
Luciferase reporter gene assay indicated that dihydrotestosterone (DHT) stimulated AR transcriptional activity dose-dependently while CAPE treatment suppressed AR transcriptional activity in Human embryonic kidney 293 (HEK293)-AR cells (Fig. 1a)
Summary
Androgen receptor (AR) plays important role in the development, progression, and metastasis of prostate cancer (PCa). We determined if CAPE affects the signaling and stability of AR in PCa cells. Binding of androgen to AR induces dissociation of AR from heat-shock proteins (HSPs) and stimulates AR phosphorylation [2]. AR dimerizes, translocates into the nucleus, and binds to androgen-response elements (ARE). AR regulates male sexual maturation, maintenance of normal prostate function, prostate carcinogenesis, and prostate cancer (PCa) progression [4, 5]. AR plays important role in the development, progression, and metastasis of PCa [2, 6, 7] and AR modulates the expression of proteins regulating cell cycle, survival, and growth [8,9,10].
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