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A novel prostate cancer therapeutic strategy using icaritin-activated arylhydrocarbon-receptor to co-target androgen receptor and its splice variants
Sun F.1; Indran I.R.1; Zhang Z.W.1; Tan M.H.E.1; Li Y.1; Lim Z.L.R.1; Hua R.1; Yang C.1; Soon F.-F.1; Li J.1; Xu H.E.3; Cheung E.2; Yong E.-L.1
2015
Source PublicationCarcinogenesis
ISSN14602180 01433334
Volume36Issue:7Pages:757-768
AbstractPersistent 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.
DOI10.1093/carcin/bgv040
URLView the original
Language英語
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Cited Times [WOS]:32   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionUniversity of Macau
Affiliation1.Yong Loo Lin School of Medicine
2.A-Star, Genome Institute of Singapore
3.Van Andel Research Institute
Recommended Citation
GB/T 7714
Sun F.,Indran I.R.,Zhang Z.W.,et al. A novel prostate cancer therapeutic strategy using icaritin-activated arylhydrocarbon-receptor to co-target androgen receptor and its splice variants[J]. Carcinogenesis,2015,36(7):757-768.
APA Sun F..,Indran I.R..,Zhang Z.W..,Tan M.H.E..,Li Y..,...&Yong E.-L..(2015).A novel prostate cancer therapeutic strategy using icaritin-activated arylhydrocarbon-receptor to co-target androgen receptor and its splice variants.Carcinogenesis,36(7),757-768.
MLA Sun F.,et al."A novel prostate cancer therapeutic strategy using icaritin-activated arylhydrocarbon-receptor to co-target androgen receptor and its splice variants".Carcinogenesis 36.7(2015):757-768.
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