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  • Knuuttila, Matias (author)

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

  • Article/chapterEnglish2018

Publisher, publication year, extent ...

  • Elsevier BV,2018

Numbers

  • LIBRIS-ID:oai:gup.ub.gu.se/262053
  • https://gup.ub.gu.se/publication/262053URI
  • https://doi.org/10.1016/j.ajpath.2017.08.036DOI

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  • Language:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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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  • Mehmood, Arfa (author)
  • Huhtaniemi, Riikka (author)
  • Yatkin, Emrah (author)
  • Häkkinen, Merja R (author)
  • Oksala, Riikka (author)
  • Laajala, Teemu D (author)
  • Ryberg, Henrik,1971Gothenburg University,Göteborgs universitet,Centre for Bone and Arthritis Research,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition(Swepub:gu)xrybhe (author)
  • Handelsman, David J (author)
  • Aittokallio, Tero (author)
  • Auriola, Seppo (author)
  • Ohlsson, Claes,1965Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Centre for Bone and Arthritis Research,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition(Swepub:gu)xohlcl (author)
  • Laiho, Asta (author)
  • Elo, Laura L (author)
  • Sipilä, Petra (author)
  • Mäkelä, Sari I (author)
  • Poutanen, MattiGothenburg University,Göteborgs universitet,Centre for Bone and Arthritis Research,Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition,Institute of Medicine, Department of Internal Medicine and Clinical Nutrition(Swepub:gu)xpouma (author)
  • Göteborgs universitetCentre for Bone and Arthritis Research (creator_code:org_t)

Related titles

  • In:The American journal of pathology: Elsevier BV188:1, s. 216-2281525-21910002-9440

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