Over-expression of TGF-beta1 in Smad4-deficient human oral carcinoma cells causes tumour regression in vivo by mechanisms that sensitize cells to apoptosis.
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.
Thavaraj
Selvam
S
Department of Oral and Dental Science, University of Bristol, Bristol, UK.
Paterson
Ian C
IC
Hague
Angela
A
Prime
Stephen S
SS
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000502:physiology*; D004357:Drug Synergism; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000502:physiology; D009365:Neoplasm Regression, Spontaneous / Q000473:pathology* / Q000503:physiopathology; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000494:pharmacology; D051901:Smad4 Protein; D015534:Trans-Activators / Q000172:deficiency / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D002945:Cisplatin