Over-expression of TGF-beta1 in Smad4-deficient human oral carcinoma cells causes tumour regression in vivo by mechanisms that sensitize cells to apoptosis

J Pathol. 2005 Jan;205(1):14-20. doi: 10.1002/path.1683.

Abstract

We have shown previously that transforming growth factor-beta (TGF-beta) is a potent tumour suppressor in Smad4-deficient human malignant oral keratinocytes but the mechanism by which this occurs is unknown. In the present study, we show that over-expression of TGF-beta1 causes regression of tumours derived from Smad4-deficient oral keratinocytes transplanted orthotopically to athymic mice. Further, tumour regression is associated with the induction of apoptosis without changes in cell proliferation. In vitro, TGF-beta1 did not induce apoptosis directly in these cells but sensitized cells to cisplatin, but not Fas, -induced cell death. The data suggest that TGF-beta1 induces tumour regression in vivo by Smad4-independent pathways that sensitize keratinocytes to mitochondrial-mediated apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Cisplatin / pharmacology
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / physiology*
  • Drug Synergism
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Mouth Neoplasms / metabolism
  • Mouth Neoplasms / pathology*
  • Neoplasm Proteins / deficiency
  • Neoplasm Proteins / physiology
  • Neoplasm Regression, Spontaneous / pathology*
  • Neoplasm Regression, Spontaneous / physiopathology
  • Neoplasm Transplantation
  • Recombinant Proteins / pharmacology
  • Smad4 Protein
  • Trans-Activators / deficiency
  • Trans-Activators / physiology*
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Transforming Growth Factor beta / physiology*
  • Transforming Growth Factor beta1
  • Transplantation, Heterologous
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • Neoplasm Proteins
  • Recombinant Proteins
  • SMAD4 protein, human
  • Smad4 Protein
  • TGFB1 protein, human
  • Tgfb1 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Cisplatin