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Acute Leukemias

The role of the nuclear Akt activation and Akt inhibitors in all-trans-retinoic acid-differentiated HL-60 cells

Leukemia volume 20, pages 941–951 (2006)Cite this article

Abstract

The pharmacological inhibitors of phosphoinositide 3-kinase (PI3K)/Akt pathway have been proposed in the treatment of leukemia based on their antiproliferative effects. However, several studies demonstrated the activation of PI3K in the nuclei of all-trans-retinoic acid (ATRA) – differentiated HL-60 cells, raising the possibility that PI3K/Akt-inhibitors may block antitumor properties of retinoids. The aim of the present study was to investigate the possible activation of nuclear Akt in ATRA-treated cells and to test the effects of Akt-inhibitors on ATRA-mediated differentiation. The Akt-activity was found to be increased in the nuclei and lysates of ATRA-differentiated HL-60 and NB4 cells. The down-modulation of the expression of Akt protein in HL-60 cells using siRNA reduces the CD11b expression in ATRA-treated cells. The treatment of both cell lines with the commercially available Akt inhibitors inhibited the growth of both control and ATRA-treated cells. Akt-inhibitors had no inhibitory effects on ATRA-mediated growth arrest and the expression of CD11b in HL-60 cells, but increased the percentage of control cells expressing CD11b. In contrast, the presence of Akt inhibitors reduced the expression of CD11b in ATRA-treated NB4 cells.

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Acknowledgements

We thank Jane Leitch, Nick Leslie and Peter Downes for valuable help and advice in performing Akt kinase assays. This work was supported by the Ministry for Science of the Republic of Croatia (to DV and HB), and by the Fogarty International Research Collaboration Award (to HB).

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Authors and Affiliations

  1. Department of Physiology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia

    K Matkovic, H Banfic & D Visnjic

  2. Department of Morphology and Embryology, Signal Transduction Unit-Laboratory of Cell Biology, Section of Human Anatomy, University of Ferrara, Via Fossato di Mortara, Ferrara, Italy

    F Brugnoli & V Bertagnolo

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  1. K Matkovic
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Correspondence to D Visnjic.

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Matkovic, K., Brugnoli, F., Bertagnolo, V. et al. The role of the nuclear Akt activation and Akt inhibitors in all-trans-retinoic acid-differentiated HL-60 cells. Leukemia 20, 941–951 (2006). https://doi.org/10.1038/sj.leu.2404204

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