Abstract
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.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anilides / adverse effects
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Anilides / metabolism
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Anilides / pharmacology*
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Animals
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Antineoplastic Agents, Hormonal / adverse effects
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Antineoplastic Agents, Hormonal / metabolism
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Antineoplastic Agents, Hormonal / pharmacology*
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Benzamides
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Cell Line, Tumor
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Chromatin Assembly and Disassembly / drug effects
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Female
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HEK293 Cells
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Hepatocyte Nuclear Factor 3-alpha / antagonists & inhibitors
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Hepatocyte Nuclear Factor 3-alpha / genetics
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Hepatocyte Nuclear Factor 3-alpha / metabolism*
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Humans
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Male
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nitriles / adverse effects
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Nitriles / metabolism
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Nitriles / pharmacology*
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Nonsteroidal Anti-Androgens / adverse effects
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Nonsteroidal Anti-Androgens / metabolism
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Nonsteroidal Anti-Androgens / pharmacology*
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Oocytes / cytology
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Oocytes / drug effects
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Oocytes / metabolism
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Phenylthiohydantoin / analogs & derivatives*
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Phenylthiohydantoin / metabolism
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Phenylthiohydantoin / pharmacology
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Prostate / drug effects
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Prostate / metabolism
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Prostate / pathology
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Prostatic Neoplasms / drug therapy*
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein Transport / drug effects
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RNA Interference
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Receptors, Androgen / genetics
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Receptors, Androgen / metabolism
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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Tosyl Compounds / adverse effects
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Tosyl Compounds / metabolism
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Tosyl Compounds / pharmacology*
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Xenopus laevis
Substances
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AR protein, human
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Anilides
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Antineoplastic Agents, Hormonal
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Benzamides
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FOXA1 protein, human
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Hepatocyte Nuclear Factor 3-alpha
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Neoplasm Proteins
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Nitriles
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Nonsteroidal Anti-Androgens
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Receptors, Androgen
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Recombinant Proteins
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Tosyl Compounds
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Phenylthiohydantoin
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enzalutamide
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bicalutamide