Normally, GSK-3β is expressed in the cytoplasm of cells. Recent AZD8186 in vivo studies have shown that GSK-3β could shuttle from the cytoplasm to the nucleus in pancreatic cancer cell lines and in most poorly differentiated human pancreatic adenocarcinomas [17], and in human CLL B cells [9]. In this study, we found aberrant nuclear accumulation of GSK-3β in cells obtained from children with ALL, whereas GSK-3β was not detected in the nucleus of control cells. GSK-3β transposition RSL 3 was thought to participate in the regulation of gene transcription through the phosphorylation of transcription factors [18]. NF-κB, an important transcription factor also involved in the regulation of cell proliferation, differentiation, and

apoptosis, is deregulated in many human tumors [19, 20]. Previous studies have suggested that NF-κB transcriptional activity is regulated by GSK-3β [7]. Genetic depletion of GSK-3β by RNA interference suppresses basal NF-κB transcriptional activity, leading to decreased pancreatic cancer cell proliferation and survival [8]. Recently, it has been demonstrated that GSK-3β positively regulates NF-κB-mediated drug resistance in acute myeloid leukemia (AML) [21]. In this study, we tested ex vivo the effect of 2 chemically distinct small-molecule inhibitors of GSK-3β

at subtoxic concentrations: LiCl, a well-known GSK-3β inhibitor, and SB216763, a widely used maleimide-containing GSK-3β inhibitor. Using the pharmacological mafosfamide inhibitors of GSK-3β, we estimated the level of GSK-3β inhibition by detecting the protein levels of click here GSK-3β in cytosolic and nuclear extracts through western blot assay. In ALL cells, we found that both inhibitors led to depletion of the nuclear pool of GSK-3β, whereas no change was found in the cytoplasm extract. Moreover, we found that GSK-3β inhibition in ALL cells did not prevent NF-κB relocation from the cytoplasm

to the nucleus, but the inhibition affected the transcriptional repression of NF-κB, as shown by EMSA analysis. Similar to previous studies [7], our studies on pediatric ALL cells show that NF-κB can be regulated by GSK-3β at the level of the nuclear transcriptional complex. The exact mechanism by which GSK-3β affects NF-κB transcriptional activity is still unknown. GSK-3β influences NF-κB-mediated gene transcription in pancreatic cancer cells at a point distal to the IκB kinase complex [7]. Recent data have demonstrated that GSK-3β may contribute to p65/p50 binding to the promoters and transcriptional activation of NF-κB in CLL cells by regulating histone modification [6]. However, the underlying mechanism by which GSK-3β regulates p65 NF-κB binding to target gene promoters has not been defined. NF-κB is known as an important factor of cancer cell survival in human tumorigenesis [22]. In this report, we found that GSK-3β suppression sensitized ALL cells to NF-κB-mediated apoptosis. Both SB216763 and LiCl have been shown to induce ALL cells apoptosis.