Endocrine Abstracts (2016) 42 P8 | DOI: 10.1530/endoabs.42.P8

Antiandrogens reduce intratumoral androgen concentrations and induce androgen receptor expression in castration-resistant VCaP xenografts

Matias Knuuttila1,2, Arfa Mehmood3, Riikka Huhtaniemi1,2,4, Riikka Oksala4, Merja Häkkinen5, Teemu D Laajala6,7, Tero Aittokallio6,7, Seppo Auriola5, Claes Ohlsson8, Laura Elo-Uhlgren3,6, Petra Sipilä1,2, Sari Mäkelä2,9 & Matti Poutanen1,2,8

1Department of Physiology, University of Turku, Turku, Finland; 2Turku Center for Disease Modeling (TCDM), Institute of Biomedicine, University of Turku, Turku, Finland; 3Turku Centre for Biotechnology, University of Turku and Æbo Akademi University, Turku, Finland; 4Orion Pharma, Turku, Finland; 5School of Pharmacy, University of Eastern Finland, Kuopio, Finland; 6Department of Mathematics and Statistics, University of Turku, Turku, Finland; 7Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; 8Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 9Functional Foods Forum, University of Turku, Turku, Finland.

The growth of prostate cancer (PCa) can be suppressed by androgen deprivation therapy (ADT). However, in a significant proportion of men receiving ADT PCa progresses to castration-resistant prostate cancer, associated with activation of intratumoral androgen biosynthesis and induced androgen receptor (AR) expression. Accordingly, we have recently shown that the castration-resistant VCaP (CR-VCaP) xenografts express high level of AR and retain detectable intratumoral androgen concentrations, and respond to antiandrogens, enzalutamide and ARN-509, as evidenced by the reduced circulating PSA concentration. In the present study we show that the expression of full-length AR (AR-FL), as well as the splice variants AR-V1 and AR-V7, was further increased 2 to 3-fold by the antiandrogens, both mRNA and protein levels, while the AR-FL still remained by far the most abundantly expressed AR form. Interestingly, the antiandrogen treated tumors presented with markedly reduced (tenfold) intratumoral testosterone and DHT concentrations as compared with the vehicle treated tumors, while no such drop was detected for androstenedione and for the precursors for androgen synthesis, such as pregnenolone, progesterone and 17-hydroxyprogesterone. For all the steroids measured the tumor concentrations were higher than that measured in the serum, indicating local synthesis. Despite of the low intratumoral concentrations, antiandrogen treatment induced only minor changes on the expression of classical androgen-regulated genes, including TMPRSS2 and KLK3, likely due to the induced expression of full-length AR and AR variants. However, global transcription analysis revealed altered expression of 291 genes, and of those, several AR-interacting genes and enzymes involved in steroid metabolism were included.

Presenting author: Matias Knuuttila, Department of Physiology, Institute of Biomedicine, University of Turku, Kiinamyllynkatu 10, 20520 Turku, Finland. Email: matias.knuuttila@utu.fi.