title: Intratumoral conversion of adrenal androgen precursors drives androgen receptor-activated cell growth in prostate cancer more potently than de novo steroidogenesis.
abstract: BACKGROUND
  Despite an initial response to hormonal therapy, patients with advanced prostate cancer (PC) almost always progress to castration-resistant disease (CRPC). Although serum testosterone (T) is reduced by androgen deprivation therapy, intratumoral T levels in CRPC are comparable to those in prostate tissue of eugonadal men. These levels could originate from intratumoral conversion of adrenal androgens and/or from de novo steroid synthesis. However, the relative contribution of de novo steroidogenesis to AR-driven cell growth is unknown.
  
  
  METHODS
  The relative contribution of androgen biosynthetic pathways to activate androgen receptor (AR)-regulated cell growth and expression of PSA, FKBP5, and TMPRSS2 was studied at physiologically relevant levels of adrenal androgen precursors and intermediates of de novo androgen biosynthesis in human prostate cancer cell lines, PC346C, VCaP, and LNCaP.
  
  
  RESULTS
  In PC346C and VCaP, responses to pregnenolone and progesterone were absent or minimal, while large effects of adrenal androgen precursors were found. VCaP CRPC clones overexpressing CYP17A1 did not acquire an increased ability to use pregnenolone or progesterone to activate AR. In contrast, all precursors stimulated growth and gene expression in LNCaP cells, presumably resulting from the mutated AR in these cells.
  
  
  CONCLUSIONS
  Our data indicate that at physiological levels of T precursors PC cells can generally convert adrenal androgens, while de novo steroidogenesis is not generally possible in PC cells and is not able to support AR transactivation and PC growth.
authors.affiliation: Department of Urology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jinpei
authors.initials: J
authors.lastname: Kumagai
authors.forename: Johannes
authors.initials: J
authors.lastname: Hofland
authors.forename: Sigrun
authors.initials: S
authors.lastname: Erkens-Schulze
authors.forename: Natasja F J
authors.initials: NF
authors.lastname: Dits
authors.forename: Jacobie
authors.initials: J
authors.lastname: Steenbergen
authors.forename: Guido
authors.initials: G
authors.lastname: Jenster
authors.forename: Yukio
authors.initials: Y
authors.lastname: Homma
authors.forename: Frank H
authors.initials: FH
authors.lastname: de Jong
authors.forename: Wytske M
authors.initials: WM
authors.lastname: van Weerden
mesh_terms: D000728:Androgens / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008297:Male; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000378:metabolism*; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; D013254:Steroid 17-alpha-Hydroxylase
keywords: androgen-independent prostate cancer; androgen-responsive genes; precursors of testosterone; proliferation; real-time RT-PCR