TOK-001 and abiraterone are potent 17-heteroarylsteroid (17-HAS) inhibitors of Cyp17, the rate determining enzyme in the biosynthesis of testosterone from cholesterol in prostate cancer cells.
Nevertheless, the molecular mechanism underlying the prevention of prostate cell growth by 17-HASs still remains elusive. Here, we assess the effects of 17-HASs on androgen receptor (AR) activity in LNCaP and LAPC-4 cells. We demonstrate that 17-HASs reduced AR protein and mRNA expression, and that they antagonize AR-dependent promoter activation induced by androgen. TOK-001, but not abiraterone, is an effective apparent competitor of the radio-ligand [3H]-R1881 for binding to the wild type and various mutant AR (W741C, W741L) proteins. In agreement with these data, TOK-001 is a superior inhibitor than abiraterone of R1881-induced transcriptional activity of both wild type and mutant AR. However, neither agent was able to trans-activate the AR in the absence of R1881. TOK-001 alters AR translation initiation as demonstrated by the reduced expression of a reporter gene fused to the AR 5' UTR. Furthermore, our observation that phospho-4EBP1 levels are significantly reduced by TOK-001 and to a lesser extent by abiraterone alcohol suggests a mechanism by which cap-dependent translation is suppressed by blocking assembly of the eIF4F complex to the mRNA 5' signaling are complex, ranging from a decrease in testosterone production through the inhibition of CYP17 as previously described, to directly reducing both AR protein expression and R1881-induced AR trans-activation.
Written by:
Soifer HS, Souleimanian N, Wu S, Voskresenskiy AM, Collak FK, Cinar B, Stein CA. Are you the author?
Montefiore-Einstein Cancer Center, United States.
Reference: J Biol Chem. 2011 Dec 15. [Epub ahead of print]
PubMed Abstract
PMID: 22174412
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