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Inhibitory effects of Ras/Raf/MEK/ERK and PI3k/Akt/mTOR signal pathways on differentiation of PMA-treated leukemia cells

The pharmacological inhibitors of Ras/Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways have been proposed in the treatment of leukemia based on their inhibitory effects on proliferation. However, several studies demonstrated the activation of ERK and PI3K during PMA-mediated differentiation of leukemia HL-60 cells, raising the possibility that inhibitors may block differentiation. The aim of the present study was to test the effects of PI3K-inhibitors LY 294002, MEK-inhibitor PD 98059 and mTOR-inhibitor rapamycin on PMA-mediated differentiation and growth arrest. Inhibitors had no effects on CD11b expression in control cells. MEK-inhibitor alone and in combination with rapamycin, significantly decreased CD11b expression in PMA-stimulated HL-60 cells, while showing no effects in NB4 cells. In contrast, PI3K-inhibitor, either alone or in combination with rapamycin, decreased CD11b expression in NB4 cell line. All inhibitors arrested proliferation of control HL-60 cells. Rapamycin alone or in combination with LY 294002 arrested NB4 cells. MEK inhibitor prevented PMA-mediated growth arrest in both cell lines. Our results demonstrate that combination of inhibitors had no better inhibitory effects on proliferation than inhibitors alone, while having more effects on blocking differentiation. Rapamycin was the only antiproliferative agent that did not prevent PMA-mediated differentiation.

leukemia; rapamycin; MEK; PI3K; PMA

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