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PI-3-kinase is an essential anti-apoptotic effector in the proliferative response of primary human epithelial cells to mutant RAS

Oncogene volume 19, pages 2269–2276 (2000)Cite this article

Abstract

In contrast to its growth-inhibitory effect on primary mesenchymal cells, RAS oncogene activation induces a proliferative phenotype in normal human thyroid epithelial cells in vitro, consistent with its putative role in tumour initiation. Using this model, we previously showed that activation of the MAP kinase (MAPK) pathway is necessary, but not sufficient for the proliferative response to mutant (V12) H-RAS. Here we extend this work to show that another major RAS effector – phosphatidylinositol-3-kinase (PI-3-K) – while also insufficient alone, is able to synergize with MAPK activation to mimic the effect of mutant RAS, albeit at reduced efficiency. Furthermore we show that PI-3-K is an absolute requirement for the proliferative response to RAS in these cells, acting via suppression of RAS-induced apoptosis. These data extend our understanding of RAS signalling in a clinically-relevant cell context and point to the use of PI-3-K inhibitors as potential therapeutic agents for targetting human cancers induced by RAS mutation.

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Acknowledgements

We thank the Cancer Research Campaign for grant support, Dr Julian Downward for supply of retroviral vectors, and Michele Haughton for thyroid cell preparation. The editorial assistance of Theresa King is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Pathology, Cancer Research Campaign Laboratories, University of Wales College of Medicine, Cardiff, CF14 4XN, UK

    Véronique Gire & David Wynford-Thomas

  2. Cancer Research Campaign Centre for Cell and Molecular Biology, Chester Beatty Laboratories, Institute of Cancer Research, London, SW3 6JB, UK

    Christopher Marshall

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  1. Véronique Gire
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Gire, V., Marshall, C. & Wynford-Thomas, D. PI-3-kinase is an essential anti-apoptotic effector in the proliferative response of primary human epithelial cells to mutant RAS. Oncogene 19, 2269–2276 (2000). https://doi.org/10.1038/sj.onc.1203544

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