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Inhibition of human bladder tumour cell growth by fibroblast growth factor receptor 2b is independent of its kinase activity. Involvement of the carboxy-terminal region of the receptor

Oncogene volume 23, pages 9201–9211 (2004)Cite this article

Abstract

The b isoform of fibroblast growth factor receptor 2, FGFR2b/FGFR2-IIIb/Ksam-IIC1/KGFR, a tyrosine kinase receptor, is expressed in a wide variety of epithelia and is downregulated in several human carcinomas including prostate, salivary and urothelial cell carcinomas. FGFR2b has been shown to inhibit growth in tumour cell lines derived from these carcinomas. Here, we investigated the molecular mechanisms underlying the inhibition of human urothelial carcinoma cell growth following FGFR2b expression. Using a nylon DNA array, we analysed the gene expression profile of the T24 bladder tumour cell line, transfected or not with a construct encoding FGFR2b. The expression of FGFR2b in T24 cells decreased insulin-like growth factor (IGF)-II mRNA levels. This decrease was correlated with a decrease in IGF-II secretion and may have been responsible for the observed inhibition of cell growth because the addition of exogenous IGF-II restored growth rates to normal levels. Using SU5402, an inhibitor of FGFR tyrosine kinase activity, and a kinase dead mutant of the receptor, FGFR2b Y659F/Y660F, we also demonstrated that the growth inhibition and decrease in IGF-II secretion induced by FGFR2b did not require tyrosine kinase activity. Finally, we demonstrated the involvement of the distal carboxy-terminal domain of the receptor in decreasing IGF-II expression and inhibiting T24 cell growth, as Ksam-IIC3, a variant of FGFR2b carrying a short carboxy-terminus, neither downregulated IGF-II nor inhibited cell proliferation. Our data suggest that FGFR2b inhibits the growth of bladder carcinoma cells by reducing IGF-II levels via its carboxy-terminal domain, independent of its tyrosine kinase activity.

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Abbreviations

FGFR:

fibroblast growth factor receptor

FGF:

fibroblast growth factor

IGF:

insulin-like growth factor

RT–PCR:

reverse transcription–polymerase chain reaction

FCS:

foetal calf serum

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Acknowledgements

We would like to thank Dr Yutaka Hattori, Dr Masaaki Terada and Dr Teruhiko Yoshida for providing the Ksam-IIC1/FGFR2b and Ksam-IIC3 plasmids, and Dr Sylvia Richardson for fruitful discussion. This work was supported by the CNRS, the Bio-ingénierie 2001 programme from the French Ministry of Education and Research (Biogen74 project) and the Ligue Contre le Cancer (laboratoire associé).

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Authors and Affiliations

  1. UMR144, CNRS Institut Curie, Section de Recherche, 26 rue d'Ulm, Paris, 75248, Cedex, France

    Isabelle Bernard-Pierrot, David Ricol, Aurélie Caillault, Séverine Lair, Jean-Paul Thiery & François Radvanyi

  2. Cancer and Infection Research Area, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK

    Andrew Cassidy, Alexander Graham & Paul Elvin

  3. Hôpital Paul Brousse, 16 Avenue Paul Vaillant Couturier, Villejuif, 94807, Cedex, France

    Philippe Broët

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  1. Isabelle Bernard-Pierrot
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Correspondence to François Radvanyi.

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Bernard-Pierrot, I., Ricol, D., Cassidy, A. et al. Inhibition of human bladder tumour cell growth by fibroblast growth factor receptor 2b is independent of its kinase activity. Involvement of the carboxy-terminal region of the receptor. Oncogene 23, 9201–9211 (2004). https://doi.org/10.1038/sj.onc.1208150

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