title: Reactivation of embryonic nodal signaling is associated with tumor progression and promotes the growth of prostate cancer cells.
abstract: BACKGROUND
  Nodal is a member of the transforming growth factor β (TGFβ) superfamily that directs embryonic patterning and promotes the plasticity and tumorigenicity of tumor cells, but its role in the prostate is unknown. The goal of this study was to characterize the expression and function of Nodal in prostate cancer and determine whether, like other TGFβ ligands, it modulates androgen receptor (AR) activity.
  
  
  METHODS
  Nodal expression was investigated using immunohistochemistry of tissue microarrays and Western blots of prostate cell lines. The functional role of Nodal was examined using Matrigel and soft agar growth assays. Cross-talk between Nodal and AR signaling was assessed with luciferase reporter assays and expression of endogenous androgen regulated genes.
  
  
  RESULTS
  Significantly increased Nodal expression was observed in cancer compared with benign prostate specimens. Nodal was only expressed by DU145 and PC3 cells. All cell lines expressed Nodal's co-receptor, Cripto-1, but lacked Lefty, a critical negative regulator of Nodal signaling. Recombinant human Nodal triggered downstream Smad2 phosphorylation in DU145 and LNCaP cells, and stable transfection of pre-pro-Nodal enhanced the growth of LNCaP cells in Matrigel and soft agar. Finally, Nodal attenuated AR signaling, reducing the activity of a PSA promoter construct in luciferase assays and down-regulating the endogenous expression of androgen regulated genes.
  
  
  CONCLUSIONS
  An aberrant Nodal signaling pathway is re-expressed and functionally active in prostate cancer cells.
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Mitchell G
authors.initials: MG
authors.lastname: Lawrence
authors.forename: Naira V
authors.initials: NV
authors.lastname: Margaryan
authors.forename: Daniela
authors.initials: D
authors.lastname: Loessner
authors.forename: Angus
authors.initials: A
authors.lastname: Collins
authors.forename: Kris M
authors.initials: KM
authors.lastname: Kerr
authors.forename: Megan
authors.initials: M
authors.lastname: Turner
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Seftor
authors.forename: Carson R
authors.initials: CR
authors.lastname: Stephens
authors.forename: John
authors.initials: J
authors.lastname: Lai
authors.forename: Lynne-Marie
authors.initials: LM
authors.lastname: Postovit
authors.forename: Judith A
authors.initials: JA
authors.lastname: Clements
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Hendrix
mesh_terms: D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D008297:Male; D055457:Nodal Protein / Q000378:metabolism / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000196:embryology / Q000378:metabolism* / Q000473:pathology*; D011944:Receptors, Androgen / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
chemical_list: C526007:NODAL protein, human; D055457:Nodal Protein; D011944:Receptors, Androgen; D016212:Transforming Growth Factor beta