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Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-γ1-driven activation of mTOR/p70S6-kinase pathway

Oncogene volume 29, pages 739–751 (2010)Cite this article

Abstract

In chronic myeloid leukemia, activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway is crucial for survival and proliferation of leukemic cells. Essential downstream molecules involve mammalian target of rapamycin (mTOR) and S6-kinase. Here, we present a comprehensive analysis of the molecular events involved in activation of these key signaling pathways. We provide evidence for a previously unrecognized phospholipase C-γ1 (PLC-γ1)-controlled mechanism of mTOR/p70S6-kinase activation, which operates in parallel to the classical Akt-dependent machinery. Short-term imatinib treatment of Bcr-Abl-positive cells caused dephosphorylation of p70S6-K and S6-protein without inactivation of Akt. Suppression of Akt activity alone did not affect phosphorylation of p70-S6K and S6. These results suggested the existence of an alternative mechanism for mTOR/p70S6-K activation. In Bcr-Abl-expressing cells, we detected strong PLC-γ1 activation, which was suppressed by imatinib. Pharmacological inhibition and siRNA knockdown of PLC-γ1 blocked p70S6-K and S6 phosphorylation. By inhibiting the Ca-signaling, CaMK and PKCs we demonstrated participation of these molecules in the pathway. Suppression of PLC-γ1 led to inhibition of cell proliferation and enhanced apoptosis. The novel pathway proved to be essential for survival and proliferation of leukemic cells and almost complete cell death was observed upon combined PLC-γ1 and Bcr-Abl inhibition. The pivotal role of PLC-γ1 was further confirmed in a mouse leukemogenesis model.

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Acknowledgements

We thank Dr E Buchdunger and J Roesel (Novartis Pharma, Basel, Switzerland) for the provision with imatinib, RAD001 and PKC 412, and Dr T Skorski (Temple University, Philadelphia, PA, USA) for Bcr-Abl expression constructs. We thank Dr M Schuler for his support during the preparation of this paper.

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Authors and Affiliations

  1. Department of Medicine (Cancer Research), West German Cancer Center, University Hospital, Essen, Germany

    B Markova & F Breitenbuecher

  2. Department of Internal Medicine III, Technical University, Munich, Germany

    C Albers & J Duyster

  3. Department of Haematology, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia

    J V Melo

  4. Department of Oncology and Hematology, University Cancer Center Hamburg-Eppendorf (UCCH), Hamburg, Germany

    T H Brümmendorf

  5. 3-rd Medical Department, Johannes Gutenberg University, Mainz, Germany

    B Markova, F Breitenbuecher, F Heidel, D Lipka, C Huber & T Fischer

  6. Department of Hematology/Oncology, Medical Center, Otto von Guericke University, Magdeburg, Germany

    F Heidel, D Lipka & T Fischer

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  1. B Markova
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Correspondence to T Fischer.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Markova, B., Albers, C., Breitenbuecher, F. et al. Novel pathway in Bcr-Abl signal transduction involves Akt-independent, PLC-γ1-driven activation of mTOR/p70S6-kinase pathway. Oncogene 29, 739–751 (2010). https://doi.org/10.1038/onc.2009.374

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