Is the activation of PI3K/PDK1/Akt signaling pathway a sufficient signal for the survival of 1α, 25-dihydroxyvitamin D₃-treated leukemia cells?

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Phosphoinositide-3 kinase (PI3K) family is considered to be involved in multiple cellular responses including cell growth, differentiation, cytoskeletal remodeling, vesicle trafficking, cell cycle control and cell survival. Recent studies showed that a sustained activation of PI3K pathway is critical for the survival of some hematopoietic cells. 1,25-dihydroxyvitamin D₃ (1,25D₃) can also promote cell survival while it induces monocytic differentiation and G1 arrest of myeloid leukemia cells. Although a complex array of cell signaling changes were found in 1,25D₃ - treated acute myeloid leukemia (AML) cells, no direct evidence was gained about the significance of the activation of PI3K and its downstream target Akt in cell survival. In this study, we found that Akt phosphorylation clearly increased in 1,25D₃ -treated HL60 cells, while there was no apparent increase in the total level of Akt. Surprisingly, the selective inhibitors of PI3K, LY294009 and Wortmannin, did not inhibit this elevated phosphorylation of Akt protein. Furthermore, the relatively high level of phosphorylated Akt in the 1,25D₃ -treated HL60 cells was neither sufficient to protect them from cell cycle arrest, nor from cell death after LY294002 or Wortmannin treatments. A signaling pathway other than PI3K/PDK1/Akt that leads to cell survival may be activated in 1,25D₃ -treated acute myeloid leukemia cells. Thus, cell survival signaling in HL60 cells needs further investigation. (Supported by NIH grant R01-CA44722 from the National Cancer Institute).