Antiandrogens Reduce Intratumoral Androgen Concentrations and Induce Androgen Receptor Expression in Castration-Resistant Prostate Cancer xenografts

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Knuuttila , M , Mehmood , A , Huhtaniemi , R , Yatkin , E , Häkkinen , M R , Oksala , R , Laajala , T D , Ryberg , H , Handelsman , D J , Aittokallio , T , Auriola , S , Ohlsson , C , Laiho , A , Elo , L L , Sipila , P , Makela , S I & Poutanen , M 2018 , ' Antiandrogens Reduce Intratumoral Androgen Concentrations and Induce Androgen Receptor Expression in Castration-Resistant Prostate Cancer xenografts ' , The American Journal of Pathology , vol. 188 , no. 1 , pp. 216-228 . https://doi.org/10.1016/j.ajpath.2017.08.036

Title: Antiandrogens Reduce Intratumoral Androgen Concentrations and Induce Androgen Receptor Expression in Castration-Resistant Prostate Cancer xenografts
Author: Knuuttila, Matias; Mehmood, Arfa; Huhtaniemi, Riikka; Yatkin, Emrah; Häkkinen, Merja R.; Oksala, Riikka; Laajala, Teemu D.; Ryberg, Henrik; Handelsman, David J.; Aittokallio, Tero; Auriola, Seppo; Ohlsson, Claes; Laiho, Asta; Elo, Laura L.; Sipila, Petra; Makela, Sari I.; Poutanen, Matti
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
Date: 2018-01
Language: eng
Number of pages: 13
Belongs to series: The American Journal of Pathology
ISSN: 0002-9440
URI: http://hdl.handle.net/10138/298243
Abstract: The development of castration-resistant prostate cancer (CRPC) is associated with the activation of intratumoral androgen biosynthesis and an increase in androgen receptor (AR) expression. We recently demonstrated that, similarly to the clinical CRPC, orthotopically grown castration-resistant VCaP (CR-VCaP) xenografts express high levels of AR and retain intratumoral androgen concentrations similar to tumors grown in intact mice. Herein, we show that antiandrogen treatment (enzalutamide or ARN-509) significantly reduced (10-fold, P <0.01) intratumoral testosterone and dihydrotestosterone concentrations in the CR-VCaP tumors, indicating that the reduction in intratumoral androgens is a novel mechanism by which antiandrogens mediate their effects in CRPC. Antiandrogen treatment also altered the expression of multiple enzymes potentially involved in steroid metabolism. Identical to clinical CRPC, the expression levels of the full-length AR (twofold, P <0.05) and the AR splice variants 1 (threefold, P <0.05) and 7 (threefold, P <0.01) were further increased in the antiandrogen-treated tumors. Nonsignificant effects were observed in the expression of certain classic androgen-regulated genes, such as TMPRSS2 and KLK3, despite the low levels of testosterone and dihydrotestosterone. However, other genes recently identified to be highly sensitive to androgen-regulated AR action, such as NOV and ST6GalNAc1, were markedly altered, which indicated reduced androgen action. Taken together, the data indicate that, besides blocking AR, antiandrogens modify androgen signaling in CR-VCaP xenografts at multiple levels.
Subject: SPLICE VARIANTS
IN-VIVO
DEPRIVATION THERAPY
MASS-SPECTROMETRY
GENE-EXPRESSION
C19 STEROIDS
TUMOR-GROWTH
PROGRESSION
TARGET
CELLS
3111 Biomedicine
3122 Cancers
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