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