title: Icaritin suppresses development of neuroendocrine differentiation of prostate cancer through inhibition of IL-6/STAT3 and Aurora kinase A pathways in TRAMP mice.
abstract: Neuroendocrine prostate cancer (NEPC) has a poor prognosis, with a median survival of less than 1 year after diagnosis. Following androgen deprivation therapy, prostate adenocarcinoma cells have been observed to develop an androgen receptor-negative, terminally differentiated and indolent neuroendocrine-like phenotype. However, several molecular events, including interleukin 6 (IL-6) stimulation, in the prostate microenvironment result in the appearance of aggressive, highly proliferative castrate-resistant NEPC. In this study, we examined the mechanistic effects of a natural prenylflavonoid, icaritin (ICT), on neuroendocrine differentiation in IL-6-induced LNCaP cells and NEPC development in the male transgenic adenocarcinoma of the mouse prostate (TRAMP) model. TRAMP mice received daily intraperitoneal injection of ICT or vehicle. ICT induced apoptosis in prostate tumor, suppressed NEPC development and, accordingly, improved overall survival in TRAMP mice. Expression of neuroendocrine markers (synaptophysin) and androgen receptor in TRAMP mice and neuroendocrine-like LNCaP cells were inhibited by ICT. Suppression of neuroendocrine and NEPC development by ICT was associated with dose-dependent inhibitory effects on abnormally elevated IL-6/STAT3 and Aurora kinase A in vitro and in vivo Since ICT demonstrated favorable pharmacokinetic and safety profiles with marked enrichment in prostate tissues, our study provides evidence for the development of prenylflavonoid as a multimodal therapeutic agent against NEPC.
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Tower Block, Level 12, 1E, Kent Ridge Road, Singapore 119704 and.
authors.forename: Feng
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Tower Block, Level 12, 1E, Kent Ridge Road, Singapore 119704 and.
authors.forename: Zhi Wei
authors.initials: ZW
authors.lastname: Zhang
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Tower Block, Level 12, 1E, Kent Ridge Road, Singapore 119704 and.
authors.forename: Ee Min
authors.initials: EM
authors.lastname: Tan
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Tower Block, Level 12, 1E, Kent Ridge Road, Singapore 119704 and.
authors.forename: Z L Ryan
authors.initials: ZLR
authors.lastname: Lim
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Tower Block, Level 12, 1E, Kent Ridge Road, Singapore 119704 and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Tower Block, Level 12, 1E, Kent Ridge Road, Singapore 119704 and.
authors.forename: Xiao Chong
authors.initials: XC
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Tower Block, Level 12, 1E, Kent Ridge Road, Singapore 119704 and.
authors.forename: Seok Eng
authors.initials: SE
authors.lastname: Chua
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Tower Block, Level 12, 1E, Kent Ridge Road, Singapore 119704 and.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau, China.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cheung
authors.affiliation: Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University of Singapore, Tower Block, Level 12, 1E, Kent Ridge Road, Singapore 119704 and.
authors.forename: Eu-Leong
authors.initials: EL
authors.lastname: Yong
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000096:biosynthesis* / Q000235:genetics; D018278:Carcinoma, Neuroendocrine / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D005419:Flavonoids / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D016708:Synaptophysin / Q000096:biosynthesis / Q000235:genetics; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D005419:Flavonoids; D015850:Interleukin-6; D011944:Receptors, Androgen; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D016708:Synaptophysin; C569015:Syp protein, mouse; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; C499403:icaritin