Reactivation of embryonic nodal signaling is associated with tumor progression and promotes the growth of prostate cancer cells

Mitchell G. Lawrence, Naira V. Margaryan, Daniela Loessner, Angus Collins, Kris M. Kerr, Megan Turner, Elisabeth A. Seftor, Carson R. Stephens, John Lai, Lynne Marie Postovit, Judith A. Clements, Mary J.C. Hendrix

Research output: Contribution to journalArticle

76 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1198-1209
Number of pages12
JournalProstate
Volume71
Issue number11
DOIs
StatePublished - Aug 1 2011

Keywords

  • androgen receptor
  • cripto-1
  • lefty
  • nodal
  • prostate cancer

ASJC Scopus subject areas

  • Oncology
  • Urology

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    Lawrence, M. G., Margaryan, N. V., Loessner, D., Collins, A., Kerr, K. M., Turner, M., Seftor, E. A., Stephens, C. R., Lai, J., Postovit, L. M., Clements, J. A., & Hendrix, M. J. C. (2011). Reactivation of embryonic nodal signaling is associated with tumor progression and promotes the growth of prostate cancer cells. Prostate, 71(11), 1198-1209. https://doi.org/10.1002/pros.21335