Inhibition of Glycogen Synthase Kinase-3β Promotes NF-κB Induced-apoptosis in Pediatric Acute Lymphocyte Leukemia Cells

HU Yan-Ni, Xu-You-Hua-*, Gu-Xiao-Yan, Li-Rui-Yan

Chinese Journal of Biochemistry and Molecular Biology ›› 2010, Vol. 26 ›› Issue (9) : 809-815.

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Chinese Journal of Biochemistry and Molecular Biology ›› 2010, Vol. 26 ›› Issue (9) : 809-815.
Research Papers

Inhibition of Glycogen Synthase Kinase-3β Promotes NF-κB Induced-apoptosis in Pediatric Acute Lymphocyte Leukemia Cells

  •  HU  Yan-Ni,   Xu-You-Hua-*,   Gu-Xiao-Yan,   Li-Rui-Yan
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Abstract

Nuclear factor-κB (NF-κB) is known as a key factor in acute lymphoblastic leukemia (ALL) cell survival. Glycogen synthase kinase-3β (GSK-3β) has recently been found to positively regulate the activity of NF-κB. Here, we have explored the effect of GSK-3β inhibition on NF-κB-induced apoptosis in ALL cells. Mononuclear cells are isolated from the heparinized bone marrow of children with ALL by density gradient centrifugation. GSK-3β significantly accumulates in nuclei of ALL cells by immunofluorescence staining method. Treatment of ALL cells with GSK-3β inhibitors, lithium chloride (LiCl) or SB216763 in vitro, leads to decrease of its nuclear pool, suppression of NF-κB transcriptional activity by Western blot and EMSA analyses. Furthermore, we observe that GSK-3β inhibition resultes in a marked reduction in the expression of the NF-κB antiapoptotic target gene SURVIVIN by RT-PCR analysis, and a dose-dependent increase in the number of apoptotic cells by Annexin V-PE/7-AAD double staining flow cytometry. These results suggest that GSK-3β inhibition could down-regulate NF-κB transcriptional activity and the gene expression of SURVIVIN, holding the potential to enhance apoptosis in pediatric ALL cells.

Key words

glycogen synthase kinase-3β(GSK-3β) / pediatric acute lymphocyte leukemia / nuclear factor-κB (NF-κB) / SURVIVIN / cell apoptosis

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HU Yan-Ni, Xu-You-Hua-*, Gu-Xiao-Yan, Li-Rui-Yan. Inhibition of Glycogen Synthase Kinase-3β Promotes NF-κB Induced-apoptosis in Pediatric Acute Lymphocyte Leukemia Cells[J]. Chinese Journal of Biochemistry and Molecular Biology, 2010, 26(9): 809-815

References

[1] Pui C H, Jeha S.New therapeutic strategies for the treatment of acute lymphoblastic leukaemia[J].Nat Rev Drug Discov,2007,6(2):149-165 [2] Weston V J,Austen B,Wei W,et al.Apoptotic resistance to ionizing radiation in pediatric B-precursor acute lymphoblastic leukemia frequently involves increased NF-KB survival pathway signaling[J].Blood,2004,104(5):1465-1473 [3] Ougolkov A V, Fernandez-Zapico M E, Savoy D N, et al.Glycogen synthase kinase-3beta participates in nuclear factor kappaB-mediated gene transcription and cell survival in pancreatic cancer cells[J].Cancer Res,2005,65(6):2076-2081 [4] Aggarwal B B.Nuclear factor-kappaB:the enemy within[J].Cancer Cell,2004,6(3):203-208 [5] 郑丽端, 童强松, 杨渝珍, 等.NF-κB决定小鼠胎肝激酶-1基因启动子的基本活性[J].中国生物化学与分子生物学报(Zheng Li-Duan, Tong Qiang-Song, Yang Yu-Zhen, et al. NF-κB determinates basic activity of mouse fetal liver kinase-1 promoter[J].Chin J Biochem Mol Biol),2007,23(8):625-630 [6] Hayden S M, Ghosh S.Shared principles in NF-κB signaling[J].Cell,2008,132(3):344-362 [7] Steinbrecher K A, Wilson W, Cogswell P C, et al.Glycogen synthase kinase 3beta functions to specify gene-specific, NF-kappaB dependent transcription[J].Mol Cell Biol,2005,25(19):8444-8455 [8] 曹琦, 丰有吉.糖原合酶激酶-3β促进卵巢癌细胞增殖的实验研究[J].中华肿瘤杂志(Cao Qi,Feng You-Ji.Glycogen synthase kinase-3β(GSK-3β)promotes proliferation of ovarian cancer cells in vitro[J].Chin J Oncol),2006,28(11):804-809 [9] Shakoori A, Ougolkov A, Yu Z W, et al.Deregulated GSK3beta activity in colorectal cancer: its association with tumor cell survival and proliferation[J].Biochem Biophys Res Commun, 2005,334(4):1365-1373 [10] De T F, Racaud-Sultan C, Chicanne G, et al.A crosstalk between the Wnt and the adhesion-dependent signaling pathways governs the chemosensitivity of acute myeloid leukemia[J].Oncogene,2006,25(22):3113-3122 [11] Ougolkov A V, Bone N D, Fernandez-Zapico M E, et al.Inhibition of glycogen synthase kinase-3 activity leads to epigenetic silencing of nuclear factor κB target genes and induction of apoptosis in chronic lymphocytic leukemia B cells[J].Blood,2007,110(2):735-742 [12] Buss H, Dorrie A, Schmitz M L, et al.Phosphorylation of serine 468 by GSK-3beta negatively regulates basal p65 NF-κB activity[J].J Biol Chem,2004,279(48):49571-49574 [13] Klein S P, Melton A D.A molecular mechanism for the effect of lithium on development [J].Proc Natl Acad Sci USA,1996,93(16):8455-8459 [14] Jope R S.Lithium and GSK-3:one inhibitor,two inhibitory actions,multiple outcomes [J].Trends Pharmacol Sci,2003,24(9):44l-443 [15] Wang Z, Smith S K, Murphy M, et al.Glycogen synthase kinase 3 in MLL leukaemia maintenance and targeted therapy[J].Nature,2008,455(7217):1205-1209 [16] Ougolkov A V, Fernandez-Zapico M E, Bilim V N, et al.Aberrant nuclear accumulation of glycogen synthase kinase-3beta in human pancreatic cancer: association with kinase activity and tumor dedifferentiation[J].Clin Cancer Res, 2006;12(17):5074-5081 [17] Hoeflich K P, Luo J, Rubie E A, et al.Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation[J].Nature,2000,406(6791):86-90
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