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Premium Regulation of androgen receptor expression by Z ‐isochaihulactone mediated by the JNK signaling pathway and might be related to cytotoxicity in prostate cancer
Author(s)
Liu PoYen,
Lin ShinnZong,
Sheu Jim JinnChyuan,
Lin ChengTung,
Lin PoCheng,
Chou YiWen,
Huang MaoHsuan,
Chiou TzyyWen,
Harn HorngJyh
Publication year2013
Publication title
the prostate
Resource typeJournals
PublisherWiley Subscription Services
Abstract BACKGROUND The androgen receptor (AR) is a main therapeutic target for treatment of prostate cancer (PCa). The natural compound isochaihulactone (K8), which has a chiral center ring and two racemic forms ( E ‐K8 and Z ‐K8), has anti‐tumor effects on multiple cancer types both in vitro and in vivo. Here, we determined which form of K8 contains significant tumor cytotoxicity and examined how this form regulates AR expression in PCa cells and xenografts. METHODS We chose the androgen‐dependent human PCa cell line LNCaP and the androgen‐independent cell lines DU145 and PC‐3 to study the anti‐tumor potency and AR regulation mediated by Z ‐K8. We measured cell viability and used flow cytometry, RT‐PCR, and Western blotting. Growth inhibition in vivo was evaluated with an LNCaP xenograft animal model. RESULTS In LNCaP cells, Z ‐K8 significantly repressed cell proliferation, induced apoptosis, repressed AR mRNA and protein expression in a time‐dependent manner, and induced JNK phosphorylation. Furthermore, treatment with a JNK inhibitor significantly abolished Z ‐K8‐induced AR downregulation. Z ‐K8 did not significantly inhibit reporter gene expression of constructs containing the AR promoter when it contained a mutated Sp1 binding site. Z ‐K8 also showed anti‐tumor effects in the xenograft animal model. CONCLUSION Z ‐K8 not only induced LNCaP apoptosis but also reduced AR expression. These results indicate that Z ‐K8 may be a potential anti‐tumor drug for PCa therapy. Prostate 73: 531–541, 2013. © 2012 Wiley Periodicals, Inc.
Subject(s)androgen receptor , apoptosis , biochemistry , biology , cancer , cancer research , cell growth , chemistry , downregulation and upregulation , du145 , flow cytometry , gene , in vivo , lncap , medicine , microbiology and biotechnology , prostate cancer , viability assay
Language(s)English
SCImago Journal Rank1.295
H-Index123
eISSN1097-0045
pISSN0270-4137
DOI10.1002/pros.22593

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