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

Oncogene volume 22, pages 3698–3711 (2003)Cite this article

Abstract

We have investigated the mechanism whereby tumor cells become resistant to the antiproliferative effects of transforming growth factor (TGF)-β, while maintaining other responses that can lead to increased malignancy and invasiveness. TGF-β 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-β-induced growth arrest, the TGF-β-Smad signaling pathway is attenuated compared with epithelial cells that are sensitive to the antiproliferative effects of TGF-β (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-β type I receptor and results in an altered expression profile of TGF-β-inducible genes required for cell cycle arrest. Most significantly, expression of the CDK inhibitor, p21Cip1/WAF1, which is required for TGF-β-induced growth arrest in these cells, is not maintained. Moreover, we show that artificially attenuating the TGF-β-Smad signaling pathway in HaCaT cells is sufficient to prevent TGF-β-induced growth arrest. Our results demonstrate that the duration of TGF-β-Smad signaling is a critical determinant of the specificity of the TGF-β response.

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Acknowledgements

We thank Mike Howell, Carl-Henrick Heldin, Nick Lemoine, Anita Roberts, Peter ten Dijke and Richard Treisman for reagents and cell lines and Nicholas Laping and Alastair Reith at GlaxoSmithKline Pharmaceuticals for SB-431542. We are very grateful to the Cancer Research UK FACS lab for FACS analysis, in particular Ayad Eddaoudi, to Yogi Jayaram and Ruth Peat for invaluable help with cell culture, to Peter Jordan and Giovanna Lalli for help with confocal microscopy, to Kelly Woodford-Richens for genomic characterization of Smad4 in SW-979 cells and to Gareth Inman for receptor characterization in CF-Pac1 cells. We thank Julian Downward, Nick Lemoine, Christophe Pierreux, Anita Roberts, Richard Treisman and members of the lab for useful discussions and/or helpful comments on the manuscript. The work was supported by the Imperial Cancer Research Fund (now Cancer Research, UK) and an MRC training Fellowship to FJN.

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  1. Francisco J Nicolás

    Present address: Centro Regional de Hemodonación, Ronda de Garay, s/n, 30003, Murcia, Spain

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  1. Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Francisco J Nicolás & Caroline S Hill

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Correspondence to Caroline S Hill.

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Nicolás, F., Hill, C. Attenuation of the TGF-β-Smad signaling pathway in pancreatic tumor cells confers resistance to TGF-β-induced growth arrest. Oncogene 22, 3698–3711 (2003). https://doi.org/10.1038/sj.onc.1206420

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