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.
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Glyceraldehyde 3-phosphate dehydrogenase
Glucocorticoid response element
Munck A, Holbrook NJ (1984) Glucocorticoid-receptor complexes in rat thymus cells. Rapid kinetic behavior and a cyclic model. J Biol Chem 259:820–831
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 109:16–22
Koehler PJ (1995) Use of corticosteroids in neuro-oncology. Anticancer Drugs 6:19–33
Martin SJ, Green DR (1995) Apoptosis and cancer: the failure of controls on cell death and cell survival. Crit Rev Oncol Hematol 18:137–153
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 91:479–489
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 139:1281–1292
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 275:1132–1136
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 274:2225–2233
Schmid W, Cole TJ, Blendy JA, Schutz G (1995) Molecular genetic analysis of glucocorticoid signalling in development. J Steroid Biochem Mol Biol 53:33–35
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 27:959–966
Gorman AM, Hirt UA, Orrenius S, Ceccatelli S (2000) Dexamethasone pre-treatment interferes with apoptotic death in glioma cells. Neuroscience 96:417–425
Gascoyne DM, Kypta RM, Vivanco MM (2003) Glucocorticoids inhibit apoptosis during fibrosarcoma development by transcriptionally activating Bcl-xL. J Biol Chem 278:18022–18029
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 8:279–288
Wolff JE, Jurgens H (1994) Dexamethasone induced partial resistance to methotrexate in C6-glioma cells. Anticancer Res 14:1585–1588
Weller M, Schmidt C, Roth W, Dichgans J (1997) Chemotherapy of human malignant glioma: prevention of efficacy by dexamethasone? Neurology 48:1704–1709
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 67:1861–1873
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 376:37–43
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 48:4646–4650
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 27:95–99
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 267:12606–12613
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 415:11–15
Wolff JE, Denecke J, Jurgens H (1996) Dexamethasone induces partial resistance to cisplatinum in C6 glioma cells. Anticancer Res 16:805–809
Park JH, Kim TH (2005) Release of cytochrome c from isolated mitochondria by etoposide. J Biochem Mol Biol 38:619–623
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 19:2286–2295
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 8:705–711
Vander Heiden MG, Chandel NS, Williamson EK, Schumacker PT, Thompson CB (1997) Bcl-xL regulates the membrane potential and volume homeostasis of mitochondria. Cell 91:627–637
Breckenridge DG, Xue D (2004) Regulation of mitochondrial membrane permeabilization by BCL-2 family proteins and caspases. Curr Opin Cell Biol 16:647–652
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 61:1699–1706
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 241:164–168
Lindenboim L, Haviv R, Stein R (1998) Bcl-xL inhibits different apoptotic pathways in rat PC12 cells. Neurosci Lett 253:37–40
Ruiz-Vela A, Opferman JT, Cheng EH, Korsmeyer SJ (2005) Proapoptotic BAX and BAK control multiple initiator caspases. EMBO Rep 6:379–385
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 273:3140–3143
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 7:1021–1028
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 142:802–811
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 143:3866–3874
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 133:467–476
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Ní Chonghaile, T., Concannon, C.G., Szegezdi, E. et al. Dexamethasone inhibits apoptosis in C6 glioma cells through increased expression of Bcl-XL. Apoptosis 11, 1247–1255 (2006). https://doi.org/10.1007/s10495-006-7233-1