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

Artikel i vetenskaplig tidskrift
Författare Matias Knuuttila
Arfa Mehmood
Riikka Huhtaniemi
Emrah Yatkin
Merja R Häkkinen
Riikka Oksala
Teemu D Laajala
Henrik Ryberg
David J Handelsman
Tero Aittokallio
Seppo Auriola
Claes Ohlsson
Asta Laiho
Laura L Elo
Petra Sipilä
Sari I Mäkelä
Matti Poutanen
Publicerad i The American journal of pathology
Volym 188
Nummer/häfte 1
Sidor 216-228
ISSN 1525-2191
Publiceringsår 2018
Publicerad vid Centre for Bone and Arthritis Research
Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition
Sidor 216-228
Språk en
Länkar dx.doi.org/10.1016/j.ajpath.2017.08...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Endokrinologi

Sammanfattning

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.

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