title: Direct regulation of androgen receptor activity by potent CYP17 inhibitors in prostate cancer cells.
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.
authors.affiliation: Montefiore Medical Center, Bronx, New York 10467, USA.
authors.forename: Harris S
authors.initials: HS
authors.lastname: Soifer
authors.forename: Naira
authors.initials: N
authors.lastname: Souleimanian
authors.forename: Sijian
authors.initials: S
authors.lastname: Wu
authors.forename: Anatoliy M
authors.initials: AM
authors.lastname: Voskresenskiy
authors.forename: Filiz Kisaayak
authors.initials: FK
authors.lastname: Collak
authors.forename: Bekir
authors.initials: B
authors.lastname: Cinar
authors.forename: Cy A
authors.initials: CA
authors.lastname: Stein
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000730:Androstadienes / Q000494:pharmacology*; D000736:Androstenes; D000737:Androstenols / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000730:Androstadienes; D000736:Androstenes; D000737:Androstenols; D001562:Benzimidazoles; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D004791:Enzyme Inhibitors; D010750:Phosphoproteins; D011944:Receptors, Androgen; D013254:Steroid 17-alpha-Hydroxylase; C089740:abiraterone; C500627:3-hydroxy-17-(1H-benzimidazole-1-yl)androsta-5,16-diene