LY294002 inhibits leukemia cell invasion and migration through early growth response gene 1 induction independent of phosphatidylinositol 3-kinase-Akt pathway.

LY294002 (LY29) is a commonly used pharmacologic inhibitor of the phosphatidylinositol 3-kinase (PI3K) and has shown antitumorigenic effect both in vivo and in vitro. Both LY29 and its inactive analogue, LY303511 (LY30), significantly up-regulated early growth response gene 1 (Egr-1) expression in HL-60 leukemic cells. However, wortmannin, another commonly used PI3K inhibitor, was not able to induce Egr-1 at the dose that completely blocked Akt phosphorylation. LY29 markedly decreased the invasive cells number through Matrigel and human umbilical vein endothelial cells (HUVECs) compared with the controls. Moreover, the inhibitory effects could be significantly abolished by Egr-1 gene silencing with siRNA technology. Our results indicated for the first time that LY29 could suppress leukemia cell invasion and migration at least in part through up-regulation of Egr-1, independent of its PI3K-Akt inhibitory activity. These data provide a novel explanation for the anticancer properties of LY29 in leukemias.