Nodal induces apoptosis and inhibits proliferation in human epithelial ovarian cancer cells via activin receptor-like kinase 7

J Clin Endocrinol Metab. 2004 Nov;89(11):5523-34. doi: 10.1210/jc.2004-0893.

Abstract

Human epithelial ovarian cancer is the most lethal female cancer. Hormones and growth factors, including the TGF-beta superfamily, have been suggested to play a role in ovarian tumorigenesis. The biological effects of TGF-beta superfamily are mediated by type I and type II serine/threonine kinase receptors and by intracellular Smad proteins. Recently, we have cloned four transcripts of human activin receptor-like kinase 7 (ALK7), a type I receptor for Nodal. In this study, we have investigated the role of Nodal and ALK7 in four ovarian cancer cell lines, OV2008, C13*, A2780-s, and A2780-cp. Overexpression of Nodal resulted in a significant decrease in the number of metabolically active cells. This effect was mimicked by a constitutively active ALK7 (ALK7-ca) but blocked by dominant negative mutants of ALK7, Smad2, or Smad3. Transient transfection of Nodal and ALK7-ca significantly decreased X-linked inhibitor of apoptosis protein (Xiap) expression, activated both caspase-3 and caspase-9, and increased apoptosis as determined by Hoechst nuclear staining and flow cytometry. In addition, Nodal and ALK7-ca also inhibited cell proliferation as measured by 5-bromo-2'-deoxyuridine (BrdU) assays. Interestingly, the effects of Nodal and ALK7-ca were more potent in chemosensitive A2780-s cells than in its chemoresistant counterpart, A2780-cp cells. These findings demonstrate that Nodal induces apoptosis and inhibits proliferation via ALK7 and Smad2/3 and that the effect of Nodal-ALK7 on apoptosis may be mediated in part by the down-regulation of Xiap and activation of caspase-9 and caspase-3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / physiology*
  • Apoptosis*
  • Caspases / physiology
  • Cell Division
  • Cell Line, Tumor
  • DNA-Binding Proteins / physiology
  • Female
  • Humans
  • Nodal Protein
  • Ovarian Neoplasms / pathology*
  • Proteins / physiology
  • Signal Transduction
  • Smad2 Protein
  • Smad3 Protein
  • Trans-Activators / physiology
  • Transforming Growth Factor beta / physiology*
  • X-Linked Inhibitor of Apoptosis Protein

Substances

  • DNA-Binding Proteins
  • NODAL protein, human
  • Nodal Protein
  • Proteins
  • SMAD2 protein, human
  • SMAD3 protein, human
  • Smad2 Protein
  • Smad3 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • ACVR1C protein, human
  • Activin Receptors, Type I
  • Caspases