Prostate cancer growth depends on androgens. Synthetic antiandrogens are used in the cancer treatment.
However, antiandrogens, such as bicalutamide (BIC), have a mixed agonist/antagonist activity. Here we compare the antiandrogenic capacity of BIC to a new antiandrogen, MDV3100 (MDV) or Enzalutamide™. By reconstitution of a hormone-regulated enhancer in Xenopus oocytes we show that both antagonists trigger the androgen receptor (AR) translocation to the nucleus, albeit with a reduced efficiency for MDV. Once in the nucleus, both AR-antagonist complexes can bind sequence specifically to DNA in vivo. The forkhead box transcription factor A (FoxA1) is a negative prognostic indicator for prostate cancer disease. FoxA1 expression presets the enhancer chromatin and makes the DNA more accessible for AR binding. In this context the BIC-AR antiandrogenic effect is seriously compromised as demonstrated by a significant chromatin remodeling and induction of a robust MMTV transcription whereas the MDV-AR complex displays a more persistent antagonistic character.
Written by:
Belikov S, Oberg C, Jääskeläinen T, Rahkama V, Palvimo JJ, Wrange O. Are you the author?
Department of Cell and Molecular Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden.
Reference: Mol Cell Endocrinol. 2013 Jan 5;365(1):95-107.
doi: 10.1016/j.mce.2012.10.002
PubMed Abstract
PMID: 23063623
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