title: CYP3A5 regulates prostate cancer cell growth by facilitating nuclear translocation of AR.
abstract: BACKGROUND
  The central role of androgen receptor (AR) signaling is established in prostate cancer growth and progression. We propose CYP3A5 is part of a feedback loop that modulates the sensitivity of AR to androgen exposure. The purpose of this study is to elucidate the mechanism of regulation of AR expression by CYP3A5.
  
  
  METHODS
  To identify the role of CYP3A5 in regulating AR signaling, CYP3A5 protein expression was inhibited using CYP3A5 siRNA and azamulin. Both cell fractionation and immunocytochemical approaches in combination with dihydrotestosterone (DHT) and R1881 treatment were used to evaluate changes in AR nuclear translocation.
  
  
  RESULTS
  CYP3A5 siRNA blocked growth of LNCaP and C4-2 cells by 30-60% (P ≤ 0.005). Azamulin, a CYP3A pharmacologic inhibitor, reduced the growth of LNCaP, C4-2 and 22RV1 lines by ∼ 40% (P ≤ 0.005). CYP3A5 siRNA inhibited growth in response to DHT and R1881 treatment in LNCaP and C4-2 by decreasing nuclear AR localization and resulting in diminished PSA and TMPRSS2 expression. Decreased AR nuclear localization resulting from CYP3A5 inhibition resulted in growth inhibition comparable to IC60 and IC40 of bicalutamide in LNCaP and C4-2 cell lines. Conversely, the CYP3A inducer rifampicin enhanced AR nuclear localization.
  
  
  CONCLUSIONS
  As CYP3A5 regulates the nuclear translocation of AR; co-targeting CYP3A5 may provide a novel strategy for enhancing the efficacy of androgen deprivation therapy. Consequentially, these data suggest that concomitant medications may impact androgen deprivation therapy's efficacy.
authors.affiliation: College of Biomedical Sciences, Roseman University of Health Sciences, Nevada.
authors.forename: Ranjana
authors.initials: R
authors.lastname: Mitra
authors.forename: Oscar B
authors.initials: OB
authors.lastname: Goodman
mesh_terms: D015153:Blotting, Western; D001952:Bridged-Ring Compounds / Q000494:pharmacology; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000502:physiology*; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D013196:Dihydrotestosterone / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D015741:Metribolone / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014230:Triazoles / Q000494:pharmacology
chemical_list: C410798:AR protein, human; D001952:Bridged-Ring Compounds; D065692:Cytochrome P-450 CYP3A Inhibitors; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D014230:Triazoles; D013196:Dihydrotestosterone; D015741:Metribolone; C489644:azamulin; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A
keywords: AR; CYP3A5; nuclear localization