Abstract
TOK-001 and abiraterone are potent 17-heteroarylsteroid (17-HAS) inhibitors of Cyp17, one of the rate-limiting enzymes 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 both TOK-001 and abiraterone reduced AR protein and mRNA expression, and antagonized AR-dependent promoter activation induced by androgen. TOK-001, but not abiraterone, is an effective apparent competitor of the radioligand [(3)H]R1881 for binding to the wild type and various mutant AR (W741C, W741L) proteins. In agreement with these data, TOK-001 is a consistently 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. Our data demonstrate that phospho-4EBP1 levels are significantly reduced by TOK-001 and to a lesser extent by abiraterone alcohol, and suggest a mechanism by which cap-dependent translation is suppressed by blocking assembly of the eIF4F and eIF4G complex to the mRNA 5' cap. Thus, the effects of these 17-HASs on AR 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.
Highlights
Abiraterone and TOK-001 are inhibitors of CYP17 activity, a crucial enzyme for the synthesis of testosterone in prostate cancer cells
TOK-001 and Abiraterone Alcohol, Two 17-HASs, Reduce androgen receptor (AR) Protein Levels—We measured the effects of treatment with these two compounds on AR expression in two prostate cancer cell lines, LNCaP and LAPC-4, that express AR and respond to androgen signaling
The decrease in AR protein correlated with a profound diminution of the expression of intracellular PSA protein in LNCaP cells (Fig. 1C), which in this cell line is dependent on AR signaling
Summary
Abiraterone and TOK-001 are inhibitors of CYP17 activity, a crucial enzyme for the synthesis of testosterone in prostate cancer cells. We assess the effects of 17-HASs on androgen receptor (AR) activity in LNCaP and LAPC-4 cells We demonstrate that both TOK-001 and abiraterone reduced AR protein and mRNA expression, and antagonized AR-dependent promoter activation induced by androgen. The effects of these 17-HASs on AR signaling are complex, ranging from a decrease in testosterone production through the inhibition of Cyp as previously described, to directly reducing both AR protein expression and R1881-induced AR trans-activation. CYP17 Inhibitors Regulate AR Signaling tic strategy would be to drastically reduce the levels AR protein in prostate cancer cells, by targeting its stability, degradation, expression and/or activity (18, 20 –21). This report extends the utility of 17-HASs beyond Cyp inhibition and provides a novel mechanism of action for antagonism of AR activity in prostate cancer cells
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