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Novel expression of N-cadherin elicits in vitro bladder cell invasion via the Akt signaling pathway

Oncogene volume 23, pages 4745–4753 (2004)Cite this article

Abstract

Novel N-cadherin expression has been linked to the invasive phenotype in bladder tumors yet a primary role for N-cadherin in invasion has not been defined in this model. To address this, N-cadherin was stably transfected into E-cadherin expressing bladder carcinoma cells. This resulted in an enhanced invasive capacity in in vitro assays that was blocked by incubation with an N-cadherin function-blocking antibody in a dose-dependent manner. Analysis of the signaling pathway(s) implicated in N-cadherin-mediated invasion in bladder carcinoma cell lines revealed no correlation between MAPK signaling and invasion, in the presence or absence of fibroblast growth factor 2. Also, while MAPK and p38 kinase inhibitors did not alter the invasive behavior of these cells, an increase in the phosphorylation of Akt at serine-473 was detected in N-cadherin transfectants, suggestive of N-cadherin-mediated Akt activation in bladder cell invasion. Incubation of N-cadherin transfectants with either PI3 kinase or Akt inhibitors resulted in a significant decrease in the invasive capacity of these cells. Exposure of cells to PP2, a src family kinase inhibitor, also decreased the invasive potential of N-cadherin transfectants and resulted in reduced phosphorylation of Akt. The involvement of Akt signaling in bladder cell invasion was also supported by the inhibition of bladder cell invasion by cells constitutively expressing an activated Akt kinase, using the PI3 kinase and Akt inhibitors and PP2. These results suggest that activation of PI3/AKT kinase following N-cadherin expression contributes to the increased invasive potential of bladder carcinoma cells.

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Acknowledgements

Alireza Moinzadeh and Ralph Zagha are Robert E Wise Research Fellows. We thank M Wheelock and K Johnson for reagents. This work was supported by NIH Grant 1DK59400. Work in A B-Z's laboratory was supported by the Israel Cancer Research Foundation and by the German Israeli Foundation for Scientific Research and Development.

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Authors and Affiliations

  1. Cell and Molecular Biology Laboratory, RE Wise MD Research and Education Institute, 31 Mall Road, Burlington, 01805, MA, USA

    Kimberly M Rieger-Christ, Monika Kosakowski & Ian C Summerhayes

  2. Department of Urology, Lahey Clinic, 41 Mall Road, Burlington, 01805, MA, USA

    Kimberly M Rieger-Christ, Peter Lee, Ralph Zagha, Alireza Moinzadeh, John Stoffel, John A Libertino & Ian C Summerhayes

  3. Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Avri Ben-Ze'ev

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  1. Kimberly M Rieger-Christ
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Correspondence to Ian C Summerhayes.

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Rieger-Christ, K., Lee, P., Zagha, R. et al. Novel expression of N-cadherin elicits in vitro bladder cell invasion via the Akt signaling pathway. Oncogene 23, 4745–4753 (2004). https://doi.org/10.1038/sj.onc.1207629

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