title: A novel prostate cancer therapeutic strategy using icaritin-activated arylhydrocarbon-receptor to co-target androgen receptor and its splice variants.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, 119074 Singapore, Singapore.
authors.forename: Feng
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, 119074 Singapore, Singapore.
authors.forename: Inthrani R
authors.initials: IR
authors.lastname: Indran
authors.affiliation: Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, 119074 Singapore, Singapore.
authors.forename: Zhi Wei
authors.initials: ZW
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, 119074 Singapore, Singapore.
authors.forename: M H Eileen
authors.initials: MH
authors.lastname: Tan
authors.affiliation: Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, 119074 Singapore, Singapore.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, 119074 Singapore, Singapore.
authors.forename: Z L Ryan
authors.initials: ZL
authors.lastname: Lim
authors.affiliation: Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, 119074 Singapore, Singapore.
authors.forename: Rui
authors.initials: R
authors.lastname: Hua
authors.affiliation: Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, 119074 Singapore, Singapore, Cancer Biology and Pharmacology, Genome Institute of Singapore, Agency for Science, Technology and Research, 138672 Singapore, Singapore and.
authors.forename: Chong
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, 119074 Singapore, Singapore.
authors.forename: Fen-Fen
authors.initials: FF
authors.lastname: Soon
authors.affiliation: Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, 119074 Singapore, Singapore.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, 333 Bostwick Avenue, N.E., Grand Rapids, MI 49503, USA.
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
authors.affiliation: Cancer Biology and Pharmacology, Genome Institute of Singapore, Agency for Science, Technology and Research, 138672 Singapore, Singapore and.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cheung
authors.affiliation: Department of Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, 119074 Singapore, Singapore, eu_leong_yong@nuhs.edu.sg.
authors.forename: Eu-Leong
authors.initials: EL
authors.lastname: Yong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D008297:Male; D016688:Mice, Inbred NOD; D058990:Molecular Targeted Therapy; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D055550:Protein Stability / Q000187:drug effects; D012326:RNA Splicing; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000970:Antineoplastic Agents; D005419:Flavonoids; D011944:Receptors, Androgen; D018336:Receptors, Aryl Hydrocarbon; D025801:Ubiquitin; C105156:UBE2C protein, human; D044763:Ubiquitin-Conjugating Enzymes; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; C499403:icaritin