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Pro-apoptotic protein BIM in apoptosis of glucocorticoid-sensitive and -resistant acute lymphoblastic leukemia CEM cells

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Abstract

Although glucocorticoids (GCs) have been used to treat acute lymphoblast leukemia (ALL) for decades, the mechanisms of GC sensitivity and resistance in ALL cells are poorly understood. This study investigated the role and mechanisms of pro-apoptotic protein BIM in apoptosis of GC-sensitive and- resistant ALL cells. The dramatic apoptosis was observed in GC-sensitive CEM-C7 cells after incubated with DEX for 48 h, while not in GC-resistant CEM-C1 cells. The significant up-regulation of BIM in CEM-C7 cells induced by DEX was also observed, but no up-regulation of BIM was detected in DEX-induced CEM-C1 cells. When treated with DEX plus RU486, a glucocorticoid receptor blocker, the apoptosis and BIM expression of CEM-C7 cells were canceled. P38MAPK-blocking pharmacon SB203580 also significantly inhibited the up-regulation of BIM in CEM-C7 cells. These suggested that the absence of BIM up-regulation is one of the important mechanisms of GC resistance, GC-GR conjugation is indispensible in both GC-induced apoptosis and up-regulation of BIM, and p38 MAPK signal pathway is also involved in this process.

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References

  1. Gaynon PS, Carrel AL. Glucocorticosteroid therapy in childhood acute lymphoblastic leukemia. Adv Exp Med Biol. 1999;457:593–605.

    Article  PubMed  CAS  Google Scholar 

  2. Smets LA, Salomons G, van den Berg J. Glucocorticoid induced apoptosis in leukemia. Adv Exp Med Biol. 1999;457:607–14.

    Article  PubMed  CAS  Google Scholar 

  3. Schrappe M, et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL Berlin-Frankfurt-Munster (BFM) study group from 1981 to 1995. Leukemia. 2000;14:2205–22.

    Article  PubMed  CAS  Google Scholar 

  4. Broome HE, et al. Inhibition of Bcl-xL expression sensitizes T-cell acute lymphoblastic leukemia cells to chemotherapeutic drugs. Leuk Res. 2002;26:311–6.

    Article  PubMed  CAS  Google Scholar 

  5. Mok CL, et al. Bad can act as a key regulator of T cell apoptosis and T cell development. J Exp Med. 1999;189:575–86.

    Article  PubMed  CAS  Google Scholar 

  6. Rogatsky I, Hittelman AB, Pearce D, Garabedian MJ. Distinct glucocorticoid receptor transcriptional regulatory surfaces mediate the cytotoxic and cytostatic effects of glucocorticoids. Mol Cell Biol. 1999;19:5036–49.

    PubMed  CAS  Google Scholar 

  7. Tagawa H, et al. Genome-wide array-based CGH for mantle cell lymphoma: identification of homozygous deletions of the proapoptotic gene BIM. Oncogene. 2005;24:1348–58.

    Article  PubMed  CAS  Google Scholar 

  8. Abrams MT, Robertson NM, Yoon K, Wickstrom E. Inhibition of Glucocorticoid-induced apoptosis by targeting the major splice variants of BIM mRNA with small interfering RNA and short hairpin RNA. J Biol Chem. 2004;279:55809–17.

    Article  PubMed  CAS  Google Scholar 

  9. Wang Z, Malone MH, He H, McColl KS, Distelhorst CW. Microarray analysis uncovers the induction of the proapoptotic BH3-only protein BIM in multiple models of glucocorticoid-induced apoptosis. J Biol Chem. 2003;278:23861–7.

    Article  PubMed  CAS  Google Scholar 

  10. Zhao YN, Li Q, Yang K. Role of pro-apoptotic protein bim in mouse thymocytes apoptosis induced by dexamethasone. J Sichuan Univ. 2007;38:851–4.

    CAS  Google Scholar 

  11. Clark AR, Lasa M. Crosstalk between glucocorticoids and mitogen-activated protein kinase signalling pathways. Curr Opin Pharmacol. 2003;3:404–11.

    Article  PubMed  CAS  Google Scholar 

  12. Rogatsky I, Logan SK, Garabedian MJ. Antagonism of glucocorticoid receptor transcriptional activation by the c-Jun N-terminal kinase. Proc Natl Acad Sci USA. 1998;95:2050–5.

    Article  PubMed  CAS  Google Scholar 

  13. Szatmary Z, Garabedian MJ, Vilcek J. Inhibition of glucocorticoid receptor-mediated transcriptional activation by p38 mitogen-activated protein (MAP) kinase. J Biol Chem. 2004;279:43708–15.

    Article  PubMed  CAS  Google Scholar 

  14. Tsitoura DC, Rothman PB. Enhancement of MEK/ERK signaling promotes glucocorticoid resistance in CD4− T cells. J Clin Invest. 2004;113:619–27.

    PubMed  CAS  Google Scholar 

  15. Kofler R. The molecular basis of glucocorticoid-induced apoptosis of lymphoblastic leukemia cells. Histochem Cell Biol. 2000;114:1–7.

    PubMed  CAS  Google Scholar 

  16. Ramdas J, Liu W, Harmon JM. Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells. Cancer Res. 1999;59:1378–85.

    PubMed  CAS  Google Scholar 

  17. Schmidt S, et al. Glucocorticoid resistance in two key models of acute lymphoblastic leukemia occurs at the level of the glucocorticoid receptor. FASEB J. 2006;20(14):2600–2.

    Article  PubMed  CAS  Google Scholar 

  18. Tissing WJ, Meijerink JP, den Boer ML, Pieters R. Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia. Leukemia. 2003;17:17–25.

    Article  PubMed  CAS  Google Scholar 

  19. Bachmann PS, Gorman R, Mackenzie KL, Lutze-Mann L, Lock RB. Dexamethasone resistance in B-cell precursor childhood acute lymphoblastic leukemia occurs downstream of ligand-induced nuclear translocation of the glucocorticoid receptor. Blood. 2005;105:2519–26.

    Article  PubMed  CAS  Google Scholar 

  20. Tissing WJ, et al. Glucocorticoid-induced glucocorticoid-receptor expression and promoter usage is not linked to glucocorticoid resistance in childhood acute lymphoblastic leukemia. Blood. 2006;108:1045–9.

    Article  PubMed  CAS  Google Scholar 

  21. Zhang L, Insel PA. The Pro-apoptotic protein BIM Is a convergence point for cAMP/protein kinase A and glucocorticoid-promoted apoptosis of lymphoid cells. J Biol Chem. 2004;279(20):20858–65.

    Article  PubMed  CAS  Google Scholar 

  22. Pellegrini M, Bouillet P, Robati M, Belz GT, Davey GM, Strasser A. Loss of Bim increases T cell production and function in interleukin 7 receptor-deficient mice. J Exp Med. 2004;200(9):1189–95.

    Article  PubMed  CAS  Google Scholar 

  23. Farooq A, Zhou MM. Structure and regulation of MAPK phosphatases. Cell Signal. 2004;16:769–79.

    Article  PubMed  CAS  Google Scholar 

  24. Fatima S, Khandekar Z, Parmentier JH, Malik KU. Cytosolic phospholipase A2 activation by the p38 kinase inhibitor SB203580 in rabbit aortic smooth muscle cells. J Pharmacol Exp Ther. 2001;298:331–8.

    PubMed  CAS  Google Scholar 

  25. Johnson GL, Lapadat R. Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science. 2002;298:1911–2.

    Article  PubMed  CAS  Google Scholar 

  26. Miller AL, et al. p38 Mitogen-activated protein kinase (MAPK) is a key mediator in glucocorticoid-induced apoptosis of lymphoid cells: correlation between p38 MAPK activation and site-specific phosphorylation of the human glucocorticoid receptor at serine 211. Mol Endocrinol. 2005;19:1569–83.

    Article  PubMed  CAS  Google Scholar 

  27. Ono K, Han J. The p38 signal transduction pathway: activation and function. Cell Signal. 2000;12:1–13.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by a grant from the Department of Science and Technology of Sichuan Province, China (No.2008JY0029-1). We thank Professor E. Brad Thompson (Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas) for his kindly gifts of ALL-CEM-C1 and CEM-C7 cell lines.

Declaration of interest

Qiang Li has received the research support from the Department of Science and Technology of Sichuan Province, China (No.2008JY0029-1). Ya-ning Zhao and Xia Guo are co-first author (contributed equally to the article). All authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Authors and Affiliations

  1. Department of Pediatric Hematology and Immunology, West China Second University Hospital, Sichuan University, 610041, Chengdu, China

    Xia Guo, Zhi-gui Ma, Ling Gu, Jiao Ge & Qiang Li

  2. Department of Phymatology, Baoji Municipal Central Hospital, 721008, Shaanxi, Baoji, China

    Ya-ning Zhao

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  1. Ya-ning Zhao
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  2. Xia Guo
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  3. Zhi-gui Ma
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  4. Ling Gu
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  5. Jiao Ge
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  6. Qiang Li
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Correspondence to Qiang Li.

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The authors Ya-ning Zhao and Xia Guo contributed equally to the article.

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Zhao, Yn., Guo, X., Ma, Zg. et al. Pro-apoptotic protein BIM in apoptosis of glucocorticoid-sensitive and -resistant acute lymphoblastic leukemia CEM cells. Med Oncol 28, 1609–1617 (2011). https://doi.org/10.1007/s12032-010-9641-x

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  • DOI: https://doi.org/10.1007/s12032-010-9641-x

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