Elsevier

Neoplasia

Volume 15, Issue 7, July 2013, Pages 761-772, IN17-IN22
Neoplasia

Cross Modulation between the Androgen Receptor Axis and Protocadherin-PC in Mediating Neuroendocrine Transdifferentiation and Therapeutic Resistance of Prostate Cancer1,2

https://doi.org/10.1593/neo.122070Get rights and content
Under a Creative Commons license
open access

Abstract

Castration-resistant prostate cancers (CRPCs) that relapse after androgen deprivation therapies (ADTs) are responsible for the majority of mortalities from prostate cancer (PCa). While mechanisms enabling recurrent activity of androgen receptor (AR) are certainly involved in the development of CRPC, there may be factors that contribute to the process including acquired neuroendocrine (NE) cell-like behaviors working through alternate (non-AR) cell signaling systems or AR-dependent mechanisms. In this study, we explore the potential relationship between the AR axis and a novel putative marker of NE differentiation, the human male protocadherin-PC (PCDH-PC), in vitro and in human situations. We found evidence for an NE transdifferentiation process and PCDH-PC expression as an early-onset adaptive mechanism following ADT and elucidate AR as a key regulator of PCDH-PC expression. PCDH-PC overexpression, in turn, attenuates the ligand-dependent activity of the AR, enabling certain prostate tumor clones to assume a more NE phenotype and promoting their survival under diverse stress conditions. Acquisition of an NE phenotype by PCa cells positively correlated with resistance to cytotoxic agents including docetaxel, a taxane chemotherapy approved for the treatment of patients with metastatic CRPC. Furthermore, knockdown of PCDH-PC in cells that have undergone an NE transdifferentiation partially sensitized cells to docetaxel. Together, these results reveal a reciprocal regulation between the AR axis and PCDH-PC signals, observed both in vitro and in vivo, with potential implications in coordinating NE transdifferentiation processes and progression of PCa toward hormonal and chemoresistance.

Abbreviations

ADT
androgen deprivation therapy
AR
androgen receptor
CRPC
castration-resistant prostate cancer
DHT
dihydrotestosterone
NE
neuroendocrine
PCDH-PC
protocadherin-PC

Cited by (0)

1

This work was supported by INSERM and Université Paris-Est Créteil, through grants from the Association pour la Recherche sur les Tumeurs de la Prostate (to S.T.), by the Fondation ARC pour la Recherche sur le Cancer (to F.V.), and by the Association Française d'Urologie (to A.D.L.T.). This work has been supported by institutional and charity grants only and there are no financial or other interest in the publication of this paper that might be considered a conflict of interest.

2

This article refers to supplementary materials, which are designated by Tables W1 to W3 and Figures W1 to W6 and are available online at www.neoplasia.com.

3

Equal contribution.