, Volume 11, Issue 7, pp 1247–1255 | Cite as

Dexamethasone inhibits apoptosis in C6 glioma cells through increased expression of Bcl-XL

  • Tríona Ní Chonghaile
  • Caoimhín G. Concannon
  • Eva Szegezdi
  • Adrienne M. Gorman
  • Afshin SamaliEmail author


The glucocorticoid dexamethasone (Dex) has been reported to modulate a number of signaling pathways and physiological processes, including apoptosis. This study was carried out to investigate the cytoprotective mechanism of Dex in C6 glioma cells. Pre-treatment of cells with Dex inhibited apoptosis induced by staurosporine, etoposide and thapsigargin. Apoptosis inhibition correlated with blockade of mitochondrial cytochrome c release, abolition of caspase-3 activity along with inhibition of caspase-9 and PARP cleavage. Dex-mediated cytoprotection coincided with the induction of the anti-apoptotic protein, Bcl-XL. The specific glucocorticoid receptor antagonist, RU486, reversed the anti-apoptotic effect of Dex and prevented Bcl-XL induction. Here, we show for the first time that knockdown of Bcl-XL expression with siRNA reversed the protective effects of the glucocorticoid in glioma cells. We conclude that Dex-mediated inhibition of apoptosis in C6 glioma cells is through induction of Bcl-XL.


Apoptosis Bcl-XL Dexamethasone Glioma siRNA 





Glyceraldehyde 3-phosphate dehydrogenase


Glucocorticoid receptor


Glucocorticoid response element


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  1. 1.
    Munck A, Holbrook NJ (1984) Glucocorticoid-receptor complexes in rat thymus cells. Rapid kinetic behavior and a cyclic model. J Biol Chem 259:820–831PubMedGoogle Scholar
  2. 2.
    De Bosscher K, Vanden Berghe W, Haegeman G (2000) Mechanisms of anti-inflammatory action and of immunosuppression by glucocorticoids: negative interference of activated glucocorticoid receptor with transcription factors. J Neuroimmunol 109:16–22PubMedCrossRefGoogle Scholar
  3. 3.
    Koehler PJ (1995) Use of corticosteroids in neuro-oncology. Anticancer Drugs 6:19–33PubMedGoogle Scholar
  4. 4.
    Martin SJ, Green DR (1995) Apoptosis and cancer: the failure of controls on cell death and cell survival. Crit Rev Oncol Hematol 18:137–153PubMedGoogle Scholar
  5. 5.
    Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489PubMedCrossRefGoogle Scholar
  6. 6.
    Wolter KG, Hsu YT, Smith CL, Nechushtan A, Xi XG, Youle RJ (1997) Movement of Bax from the cytosol to mitochondria during apoptosis. J Cell Biol 139:1281–1292PubMedCrossRefGoogle Scholar
  7. 7.
    Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275:1132–1136PubMedCrossRefGoogle Scholar
  8. 8.
    Finucane DM, Bossy-Wetzel E, Waterhouse NJ, Cotter TG, Green DR (1999) Bax-induced caspase activation and apoptosis via cytochrome c release from mitochondria is inhibitable by Bcl-xL. J Biol Chem 274:2225–2233PubMedCrossRefGoogle Scholar
  9. 9.
    Schmid W, Cole TJ, Blendy JA, Schutz G (1995) Molecular genetic analysis of glucocorticoid signalling in development. J Steroid Biochem Mol Biol 53:33–35PubMedCrossRefGoogle Scholar
  10. 10.
    Yamamoto M, Fukuda K, Miura N, Suzuki R, Kido T, Komatsu Y (1998) Inhibition by dexamethasone of transforming growth factor beta1-induced apoptosis in rat hepatoma cells: a possible association with Bcl-xL induction. Hepatology 27:959–966PubMedCrossRefGoogle Scholar
  11. 11.
    Gorman AM, Hirt UA, Orrenius S, Ceccatelli S (2000) Dexamethasone pre-treatment interferes with apoptotic death in glioma cells. Neuroscience 96:417–425PubMedCrossRefGoogle Scholar
  12. 12.
    Gascoyne DM, Kypta RM, Vivanco MM (2003) Glucocorticoids inhibit apoptosis during fibrosarcoma development by transcriptionally activating Bcl-xL. J Biol Chem 278:18022–18029PubMedCrossRefGoogle Scholar
  13. 13.
    Bailly-Maitre B, de Sousa G, Boulukos K, Gugenheim J, Rahmani R (2001) Dexamethasone inhibits spontaneous apoptosis in primary cultures of human and rat hepatocytes via Bcl-2 and Bcl-xL induction. Cell Death Differ 8:279–288PubMedCrossRefGoogle Scholar
  14. 14.
    Wolff JE, Jurgens H (1994) Dexamethasone induced partial resistance to methotrexate in C6-glioma cells. Anticancer Res 14:1585–1588PubMedGoogle Scholar
  15. 15.
    Weller M, Schmidt C, Roth W, Dichgans J (1997) Chemotherapy of human malignant glioma: prevention of efficacy by dexamethasone? Neurology 48:1704–1709PubMedGoogle Scholar
  16. 16.
    Chen QM, Alexander D, Sun H, Xie L, Lin Y, Terrand J, Morrissy S, Purdom S (2005) Corticosteroids inhibit cell death induced by doxorubicin in cardiomyocytes: induction of antiapoptosis, antioxidant, and detoxification genes. Mol Pharmacol 67:1861–1873PubMedCrossRefGoogle Scholar
  17. 17.
    Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA et al (1995) Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37–43PubMedCrossRefGoogle Scholar
  18. 18.
    Sako T, Tauber AI, Jeng AY, Yuspa SH, Blumberg PM (1988) Contrasting actions of staurosporine, a protein kinase C inhibitor, on human neutrophils and primary mouse epidermal cells. Cancer Res 48:4646–4650PubMedGoogle Scholar
  19. 19.
    Jaxel C, Taudou G, Portemer C, Mirambeau G, Panijel J, Duguet M (1988) Topoisomerase inhibitors induce irreversible fragmentation of replicated DNA in concanavalin A stimulated splenocytes. Biochemistry 27:95–99PubMedCrossRefGoogle Scholar
  20. 20.
    Sagara Y, Fernandez-Belda F, de Meis L, Inesi G (1992) Characterization of the inhibition of intracellular Ca2+ transport ATPases by thapsigargin. J Biol Chem 267:12606–12613PubMedGoogle Scholar
  21. 21.
    Chang TC, Hung MW, Jiang SY, Chu JT, Chu LL, Tsai LC (1997) Dexamethasone suppresses apoptosis in a human gastric cancer cell line through modulation of bcl-x gene expression. FEBS Lett 415:11–15PubMedCrossRefGoogle Scholar
  22. 22.
    Wolff JE, Denecke J, Jurgens H (1996) Dexamethasone induces partial resistance to cisplatinum in C6 glioma cells. Anticancer Res 16:805–809PubMedGoogle Scholar
  23. 23.
    Park JH, Kim TH (2005) Release of cytochrome c from isolated mitochondria by etoposide. J Biochem Mol Biol 38:619–623PubMedGoogle Scholar
  24. 24.
    Hacki J, Egger L, Monney L, Conus S, Rosse T, Fellay I, Borner C (2000) Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene 19:2286–2295PubMedCrossRefGoogle Scholar
  25. 25.
    Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ (2001) BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 8:705–711PubMedCrossRefGoogle Scholar
  26. 26.
    Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB (1997) Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell 91:627–637CrossRefGoogle Scholar
  27. 27.
    Breckenridge DG, Xue D (2004) Regulation of mitochondrial membrane permeabilization by BCL-2 family proteins and caspases. Curr Opin Cell Biol 16:647–652PubMedCrossRefGoogle Scholar
  28. 28.
    Li X, Marani M, Mannucci R, Kinsey B, Andriani F, Nicoletti I, Denner L, Marcelli M (2001) Overexpression of BCL-X(L) underlies the molecular basis for resistance to staurosporine-induced apoptosis in PC-3 cells. Cancer Res 61:1699–1706PubMedGoogle Scholar
  29. 29.
    Robertson JD, Datta K, Kehrer JP (1997) Bcl-xL overexpression restricts heat-induced apoptosis and influences hsp70, bcl-2, and Bax protein levels in FL5.12 cells. Biochem Biophys Res Commun 241:164–168PubMedCrossRefGoogle Scholar
  30. 30.
    Lindenboim L, Haviv R, Stein R (1998) Bcl-xL inhibits different apoptotic pathways in rat PC12 cells. Neurosci Lett 253:37–40PubMedCrossRefGoogle Scholar
  31. 31.
    Ruiz-Vela A, Opferman JT, Cheng EH, Korsmeyer SJ (2005) Proapoptotic BAX and BAK control multiple initiator caspases. EMBO Rep 6:379–385PubMedCrossRefGoogle Scholar
  32. 32.
    Ng FW, Shore GC (1998) Bcl-XL cooperatively associates with the Bap31 complex in the endoplasmic reticulum, dependent on procaspase-8 and Ced-4 adaptor. J Biol Chem 273:3140–3143PubMedCrossRefGoogle Scholar
  33. 33.
    White C, Li C, Yang J, Petrenko NB, Madesh M, Thompson CB, Foskett JK (2005) The endoplasmic reticulum gateway to apoptosis by Bcl-X(L) modulation of the InsP3R. Nat Cell Biol 7:1021–1028PubMedCrossRefGoogle Scholar
  34. 34.
    Sasson R, Tajima K, Amsterdam A (2001) Glucocorticoids protect against apoptosis induced by serum deprivation, cyclic adenosine 3’,5’-monophosphate and p53 activation in immortalized human granulosa cells: involvement of Bcl-2. Endocrinology 142:802–811PubMedCrossRefGoogle Scholar
  35. 35.
    Webster JC, Huber RM, Hanson RL, Collier PM, Haws TF, Mills JK, Burn TC, Allegretto EA (2002) Dexamethasone and tumor necrosis factor-alpha act together to induce the cellular inhibitor of apoptosis-2 gene and prevent apoptosis in a variety of cell types. Endocrinology 143:3866–3874PubMedCrossRefGoogle Scholar
  36. 36.
    Messmer UK, Pereda-Fernandez C, Manderscheid M, Pfeilschifter J (2001) Dexamethasone inhibits TNF-alpha-induced apoptosis and IAP protein downregulation in MCF-7 cells. Br J Pharmacol 133:467–476PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Tríona Ní Chonghaile
    • 1
  • Caoimhín G. Concannon
    • 1
  • Eva Szegezdi
    • 1
  • Adrienne M. Gorman
    • 1
  • Afshin Samali
    • 2
    Email author
  1. 1.Department of Biochemistry and National Centre for Biomedical Engineering ScienceNational University of IrelandGalwayIreland
  2. 2.Cell Stress and Apoptosis Research GroupDepartment of Biochemistry, NUIGalwayIreland

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