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

Francisco J Nicolás, Caroline S Hill
Oncogene 2003 June 12, 22 (24): 3698-711
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.

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