Neurotensin and its receptors mediate neuroendocrine transdifferentiation in prostate cancer

Shimiao Zhu,Yuanjie Niu,Chuanliang Xu,Amilcar Flores-Morales,Zhiqun Shang,Chawnshang Chang,Yinghao Sun,Xiaodan Niu,Shancheng Ren,Hao Tian,Xuanrong Chen,Jiang Wang,Simeng Wen,Xing Li,Ning Jiang

doi:10.1038/s41388-019-0750-5

Abstract

Castration-resistant prostate cancer (CRPC) with neuroendocrine differentiation (NED) is a lethal disease for which effective therapies are urgently needed. The mechanism underlying development of CRPC with NED, however, remains largely uncharacterized. In this study, we explored and characterized the functional role of neurotensin (NTS) in cell line and animal models of CRPC with NED. NTS was acutely induced by androgen deprivation in animal models of prostate cancer (PCa) and activated downstream signaling leading to NED through activation of neurotensin receptor 1 (NTSR1) and neurotensin receptor 3 (NTSR3), but not neurotensin receptor 2 (NTSR2). Our findings also revealed the existence of a CK8+/CK14+ subpopulation in the LNCaP cell line that expresses high levels of both NTSR1 and NTSR3, and displays an enhanced susceptibility to develop neuroendocrine-like phenotypes upon treatment with NTS. More importantly, NTSR1 pathway inhibition prevented the development of NED and castration resistance in vivo. We propose a novel role of NTS in the development of CRPC with NED, and a possible strategy to prevent the onset of NED by targeting the NTS signaling pathway.

Highlights

These authors contributed : Shimiao Zhu, Hao Tian, Xiaodan Niu
NTS expression is elevated in Castration-resistant prostate cancer (CRPC) xenografts and correlated with NE transdifferentiation We have previously shown that castration-resistant LNCaP xenografts (CRLX) could be established and serially transplanted under castrate conditions according to the schema shown in Fig. 1a [22]
Concomitant elevation of neuron-specific enolase (NSE) and CGA, traditional neuroendocrine differentiation (NED) markers, were demonstrated in CRLX specimens, these markers were not elevated at 7 days after castration (Fig. 1c), suggesting elevation of NTS occurs earlier than other NED markers after castration

Summary

1234567890();,: 1234567890();,: Introduction

Neuroendocrine (NE)-like PCa is identified by increased staining of neuroendocrine differentiation (NED) markers, e.g. neuron-specific enolase (NSE), chromogranin A (CgA), and synaptophysin (Syn), and is believed to originate from trans-differentiated tumor cells that give rise to CRPC following ADT [6, 7]. An integrated understanding of acquired NED in the context of castration is lacking Such insights might be used for designing more effective therapies to overcome resistance and improve survival from palliative to curative measures in PCa. In this study, we delineated how NTS induces NED development after ADT in cell line and animal models of CRPC with NED. Blocking NTS signaling with NTSR1 inhibitor in combination with ADT markedly delayed NED development and reduced tumor burden in preclinical models

Results

Discussion

Methods

Compliance with ethical standards