FoxA1 corrupts the antiandrogenic effect of bicalutamide but only weakly attenuates the effect of MDV3100 (Enzalutamide™).
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.
Department of Cell and Molecular Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden.
S
S
Belikov
C
C
Öberg
T
T
Jääskeläinen
V
V
Rahkama
J J
JJ
Palvimo
Ö
Ö
Wrange
D000813:Anilides / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009570:Nitriles / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D057466:Nonsteroidal Anti-Androgens / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014105:Tosyl Compounds / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D014982:Xenopus laevis
C410798:AR protein, human; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D009363:Neoplasm Proteins; D009570:Nitriles; D057466:Nonsteroidal Anti-Androgens; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D014105:Tosyl Compounds; D010669:Phenylthiohydantoin; C540278:enzalutamide; C053541:bicalutamide