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

Abstract

We have investigated the mechanism whereby tumor cells become resistant to the antiproliferative effects of transforming growth factor (TGF)-, while maintaining other responses that can lead to increased malignancy and invasiveness. TGF- 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--induced growth arrest, the TGF--Smad signaling pathway is attenuated compared with epithelial cells that are sensitive to the antiproliferative effects of TGF- (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- type I receptor and results in an altered expression profile of TGF--inducible genes required for cell cycle arrest. Most significantly, expression of the CDK inhibitor, p21^Cip1/WAF1, which is required for TGF--induced growth arrest in these cells, is not maintained. Moreover, we show that artificially attenuating the TGF--Smad signaling pathway in HaCaT cells is sufficient to prevent TGF--induced growth arrest. Our results demonstrate that the duration of TGF--Smad signaling is a critical determinant of the specificity of the TGF- response.