A novel prostate cancer therapeutic strategy using icaritin-activated arylhydrocarbon-receptor to co-target androgen receptor and its splice variants

Persistent androgen receptor (AR) signaling is the key driving force behind progression and development of castration-resistant prostate cancer (CRPC). In many patients, AR COOH-terminal truncated splice variants (ARvs) play a critical role in contributing to the resistance against androgen depletio...

Full description

Saved in:
Bibliographic Details
Published in:Carcinogenesis (New York) 2015-07, Vol.36 (7), p.757-768
Main Authors: Sun, Feng, Indran, Inthrani R, Zhang, Zhi Wei, Tan, M H Eileen, Li, Yu, Lim, Z L Ryan, Hua, Rui, Yang, Chong, Soon, Fen-Fen, Li, Jun, Xu, H Eric, Cheung, Edwin, Yong, Eu-Leong
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
Apoptosis - genetics
Cell Line, Tumor - drug effects
Flavonoids - pharmacology
Gene Expression Regulation, Neoplastic - drug effects
Humans
Kallikreins - genetics
Kallikreins - metabolism
Male
Mice, Inbred NOD
Molecular Targeted Therapy
Original Manuscript
Prostate-Specific Antigen - genetics
Prostate-Specific Antigen - metabolism
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - metabolism
Prostatic Neoplasms - pathology
Protein Stability - drug effects
Receptors, Androgen - genetics
Receptors, Androgen - metabolism
Receptors, Aryl Hydrocarbon - genetics
Receptors, Aryl Hydrocarbon - metabolism
RNA Splicing
Signal Transduction - drug effects
Ubiquitin - metabolism
Ubiquitin-Conjugating Enzymes - genetics
Ubiquitin-Conjugating Enzymes - metabolism
Xenograft Model Antitumor Assays
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Persistent androgen receptor (AR) signaling is the key driving force behind progression and development of castration-resistant prostate cancer (CRPC). In many patients, AR COOH-terminal truncated splice variants (ARvs) play a critical role in contributing to the resistance against androgen depletion therapy. Unfortunately, clinically used antiandrogens like bicalutamide (BIC) and enzalutamide (MDV), which target the ligand binding domain, have failed to suppress these AR variants. Here, we report for the first time that a natural prenylflavonoid, icaritin (ICT), can co-target both persistent AR and ARvs. ICT was found to inhibit transcription of key AR-regulated genes, such as KLK3 [prostate-specific antigen (PSA)] and ARvs-regulated genes, such as UBE2C and induce apoptosis in AR-positive prostate cancer (PC) cells. Mechanistically, ICT promoted the degradation of both AR and ARvs by binding to arylhydrocarbon-receptor (AhR) to mediate ubiquitin-proteasomal degradation. Therefore, ICT impaired AR transactivation in PC cells. Knockdown of AhR gene restored AR stability and partially prevented ICT-induced growth suppression. In clinically relevant murine models orthotopically implanted with androgen-sensitive and CRPC cells, ICT was able to target AR and ARvs, to inhibit AR signaling and tumor growth with no apparent toxicity. Our results provide a mechanistic framework for the development of ICT, as a novel lead compound for AR-positive PC therapeutics, especially for those bearing AR splice variants.
ISSN:0143-3334
1460-2180
DOI:10.1093/carcin/bgv040