کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2196221 | 1098800 | 2013 | 13 صفحه PDF | دانلود رایگان |
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.
► The effect of bicalutamide is corrupted by FoxA1 while that of MDV3100 is reduced.
► MDV3100-AR complex binds specifically to the androgen response elements in vivo.
► Antagonists trigger AR nuclear translocation albeit with a reduced efficiency for MDV.
► Reduced chromatin remodeling correlates with the antiandrogenic effect on transcription.
► FoxA1 chromatin presetting attenuates the effect of antiandrogens.
Journal: Molecular and Cellular Endocrinology - Volume 365, Issue 1, 5 January 2013, Pages 95–107