Attenuation of the TGF-beta-Smad signaling pathway in pancreatic tumor cells confers resistance to TGF-beta-induced growth arrest

Oncogene. 2003 Jun 12;22(24):3698-711. doi: 10.1038/sj.onc.1206420.

Abstract

We have investigated the mechanism whereby tumor cells become resistant to the antiproliferative effects of transforming growth factor (TGF)-beta, while maintaining other responses that can lead to increased malignancy and invasiveness. TGF-beta signaling results in nuclear accumulation of active Smad complexes which regulate transcription of target genes. Here we show that in two pancreatic carcinoma cell lines, PT45 and Panc-1, that are resistant to TGF-beta-induced growth arrest, the TGF-beta-Smad signaling pathway is attenuated compared with epithelial cells that are sensitive to the antiproliferative effects of TGF-beta (HaCaT and Colo-357). In PT45 and Panc-1 cells, active Smad complexes remain nuclear for only 1-2 h compared with more than 6 h in HaCaT and Colo-357 cells. The attenuated pathway in PT45 and Panc-1 cells correlates with low levels of TGF-beta type I receptor and results in an altered expression profile of TGF-beta-inducible genes required for cell cycle arrest. Most significantly, expression of the CDK inhibitor, p21(Cip1/WAF1), which is required for TGF-beta-induced growth arrest in these cells, is not maintained. Moreover, we show that artificially attenuating the TGF-beta-Smad signaling pathway in HaCaT cells is sufficient to prevent TGF-beta-induced growth arrest. Our results demonstrate that the duration of TGF-beta-Smad signaling is a critical determinant of the specificity of the TGF-beta response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / analysis
  • Cell Cycle / drug effects
  • Cell Division / drug effects
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins / analysis
  • DNA-Binding Proteins / physiology*
  • Humans
  • Pancreatic Neoplasms / pathology*
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / analysis
  • Smad4 Protein
  • Trans-Activators / physiology*
  • Transcription, Genetic
  • Transforming Growth Factor beta / pharmacology*
  • Tumor Cells, Cultured

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Cyclins
  • DNA-Binding Proteins
  • Receptors, Transforming Growth Factor beta
  • SMAD4 protein, human
  • Smad4 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I