Icaritin suppresses development of neuroendocrine differentiation of prostate cancer through inhibition of IL-6/STAT3 and Aurora kinase A pathways in TRAMP mice

• Published in: Carcinogenesis (New York) 2016-07, Vol.37 (7), p.701-711
• Main Authors: Sun, Feng, Zhang, Zhi Wei, Tan, Ee Min, Lim, Z L Ryan, Li, Yu, Wang, Xiao Chong, Chua, Seok Eng, Li, Jun, Cheung, Edwin, Yong, Eu-Leong
• Format: Article
• Language: English
• Subjects: Animals; Aurora Kinase A - biosynthesis; Aurora Kinase A - genetics; Carcinoma, Neuroendocrine - drug therapy; Carcinoma, Neuroendocrine - genetics; Carcinoma, Neuroendocrine - pathology; Cell Differentiation - drug effects; Flavonoids - administration & dosage; Gene Expression Regulation, Neoplastic - drug effects; Humans; Interleukin-6 - biosynthesis; Interleukin-6 - genetics; Male; Mice; Mice, Transgenic; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Receptors, Androgen - biosynthesis; Receptors, Androgen - genetics; Signal Transduction; STAT3 Transcription Factor - biosynthesis; STAT3 Transcription Factor - genetics; Synaptophysin - biosynthesis; Synaptophysin - genetics; Tumor Microenvironment - drug effects
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgw044

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.