國家衛生研究院 NHRI:Item 3990099045/14477
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    题名: Caffeic acid phenethyl ester suppresses drug resistance of enzalutamide or abiraterone in prostate cancer cells
    作者: Chuu, CP;Kuo, YY;Huo, C
    贡献者: Institute of Cellular and Systems Medicine
    摘要: Enzalutamide (ENZ) and Abiraterone acetate (AA) are drugs targeting androgen receptor axis for treatment of metastatic castration-resistant prostate cancer (mCRPC). However, a majority of patients receiving these treatments will eventually acquire drug resistance, which is caused by multiple mechanisms including the activation of AR splice variant 7 (AR-V7). We determined if caffeic acid phenethyl ester (CAPE) can suppress the signaling of AR-V7 and tumor growth of ENZ-resistant or AA-resistant mCRPC cells. CAPE treatment dose-dependently suppressed the transcriptional activity of AR-V7, its target gene UBE2C and TMPRSS2, and its splicing factors U2AF65, SF2 and HNRNPF. Cyclohexamide treatment and MG132 treatment revealed that stability of AR-V7 was reduced by CAPE and CAPE increased AR-V7 tagged for the proteasomal degradation. Fluorescence microscopy demonstrated that treatment with CAPE reduced nuclear accumulation of AR-V7 as well as phosphorylation of Ser81 and Ser213 on AR-V7, which decreases the stability and abundance of AR-V7. CAPE inhibits the expression of CDK1 and AKT, the two kinases phosphorylating Ser81 and Ser213 on AR, respectively. Overexpression of CDK1, AKT, or c-Myc rescued the AR-V7 protein level under CAPE treatment. Injection of CAPE repressed tumor growth of 22Rv1 xenografts as well as AR-V7, CDK1 and AKT expression in tumors. Combined treatment of CAPE and ENZ or AA suppress the proliferation of enzalutamide-resistant or Abiraterone-resistant CRPC cells via inhibition of AR-V7. Our results suggested that CAPE treatment reduced expression level, stability and transcriptional activity of AR-V7 in CRPC cells, and thus prevented implying the development of resistance against enzalutamide and abiraterone via inhibition of AR-V7. CAPE may be a promising therapeutic agent for enzalutamide-resistant or abiraterone-resistant CRPC.
    日期: 2022-07
    關聯: Annals of Oncology. 2022 Jul;33(Suppl. 6):S493-S494.
    Link to: http://dx.doi.org/10.1016/j.annonc.2022.05.148
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0923-7534&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000834940400248
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