Regulation of androgen receptor expression by Z-isochaihulactone mediated by the JNK signaling pathway and might be related to cytotoxicity in prostate cancer.

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.

• Authors: Po-Yen Liu, Shinn-Zong Lin, Jim Jinn-Chyuan Sheu, Cheng-Tung Lin, Po-Cheng Lin, Yi-Wen Chou, Mao-Hsuan Huang, Tzyy-Wen Chiou, Horng-Jyh Harn
• Journal: The Prostate (Prostate) Vol. 73 Issue 5 Pg. 531-41 (Apr 2013) ISSN: 1097-0045 [Electronic] United States
• PMID: 23038474 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Wiley Periodicals, Inc.

Chemical References

• AR protein, human
• Antineoplastic Agents
• Benzodioxoles
• Cytotoxins
• Receptors, Androgen
• isochaihulactone
• Green Fluorescent Proteins
• 4-Butyrolactone

Topics

• 4-Butyrolactone (analogs & derivatives, chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Benzodioxoles (chemistry, pharmacology)
• Cell Line, Tumor
• Cytotoxins (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Green Fluorescent Proteins (genetics)
• Humans
• MAP Kinase Signaling System (physiology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Prostatic Neoplasms (drug therapy, genetics, metabolism)
• Receptors, Androgen (genetics, metabolism)
• Transcription, Genetic (drug effects)
• Xenograft Model Antitumor Assays