title: Differentiation decreased telomerase activity in rat glioblastoma C6 cells and increased sensitivity to IFN-gamma and taxol for apoptosis.
abstract: Glioblastoma is the deadliest and most prevalent brain tumor, which is not yet amenable to any treatments. Therefore, new and innovative therapeutic strategies need to be developed for treating this deadly disease. We found that all-trans retinoic acid (ATRA) or 13-cis retinoic acid (13-CRA) induced astrocytic differentiation with down regulation of telomerase activity in rat glioblastoma C6 cells and enhanced sensitivity of the cells to interferon-gamma (IFN-gamma) or taxol (TXL) for apoptosis. Sensitivity of differentiated cells to IFN-gamma or TXL was greatly increased for apoptosis with increases in calcineurin expression, Bax:Bcl-2 ratio, mitochondrial release of cytochrome c, and expression and activity of calpain and caspases. Treatment with IFN-gamma activated caspase-8 indicating induction of apoptosis via the receptor-mediated pathway. Notably, IFN-gamma activated the signal transducer and activator of transcription-1 (STAT-1) for signaling via binding to gamma activator sequence (GAS), whereas TXL activated Raf-1 kinase for inactivation of Bcl-2 by its phosphorylation. We confirmed involvement of different proteolytic mechanisms in cell death by pretreating the cells with caspase-8 inhibitor II, calpeptin (calpain inhibitor), and caspase-9 inhibitor I, and caspase-3 inhibitor IV. Results demonstrated that retinoids induced astrocytic differentiation with down regulation of telomerase activity and worked synergistically to enhance sensitivity of cells to the cytotoxic agent IFN-gamma and the cytostatic agent TXL for apoptosis. This combination therapy for differentiation and apoptosis could be highly effective for controlling the malignant growth of glioblastoma.
authors: Department of Neurosciences, Medical University of South Carolina, P.O. Box 250606, Charleston, SC 29425, USA.
authors: Arabinda
authors: A
authors: Das
authors: Naren L
authors: NL
authors: Banik
authors: Swapan K
authors: SK
authors: Ray
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000201:enzymology* / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation / Q000187:drug effects; D005909:Glioblastoma / Q000201:enzymology* / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins; D012176:Retinoids / Q000494:pharmacology; D019098:Telomerase / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D012176:Retinoids; D007371:Interferon-gamma; D019908:Proto-Oncogene Proteins c-raf; D019098:Telomerase; D053181:Caspase 8; D017239:Paclitaxel; D002118:Calcium
references: Mol Cell Biol. 2003 Feb;23(4):1278-91
references: 12556488
references: Trends Biochem Sci. 2001 Jan;26(1):61-6
references: 11165519
references: Clin Cancer Res. 1997 Nov;3(11):2033-8
references: 9815594
references: J Neurochem. 1994 Nov;63(5):1975-8
references: 7931355
references: Cancer Res. 2000 Apr 1;60(7):2040-8
references: 10766196
references: J Neurosci. 2001 Jul 1;21(13):4657-67
references: 11425893
references: J Neuroimmunol. 1985 Jun;8(4-6):283-92
references: 2989328
references: Leuk Res. 1998 Aug;22(8):711-7
references: 9680098
references: Science. 1999 Apr 9;284(5412):339-43
references: 10195903
references: J Cell Biol. 1999 Mar 8;144(5):891-901
references: 10085289
references: Br J Cancer. 2003 Feb 24;88(4):516-20
references: 12592364
references: Mol Pharmacol. 1995 Jun;47(6):1106-11
references: 7603448
references: J Neurosci Res. 2002 Nov 15;70(4):561-9
references: 12404510
references: Mol Cell Biol. 1999 Jan;19(1):431-40
references: 9858567
references: Mol Cancer. 2004 Dec 08;3(1):36
references: 15588281
references: Blood. 1981 Jun;57(6):1000-4
references: 6939451
references: Neurosci Lett. 1993 Oct 1;160(2):131-4
references: 8247342
references: J Pharmacol Sci. 2004 Oct;96(2):106-14
references: 15467265
references: Hum Pathol. 1982 May;13(5):454-8
references: 6281168
references: Br J Pharmacol. 1997 Jul;121(5):841-7
references: 9222538
references: J Biol Chem. 2001 Aug 17;276(33):30724-8
references: 11404357
references: Curr Opin Oncol. 1999 May;11(3):162-7
references: 10328589
references: J Interferon Cytokine Res. 1997 Mar;17(3):121-34
references: 9085936
references: J Biochem. 1997 Apr;121(4):677-83
references: 9163517
references: Prog Clin Biol Res. 1991;366:203-11
references: 2068138
references: Oncogene. 1998 Dec 10;17(23):2973-9
references: 9881699
references: J Gen Virol. 2003 Feb;84(Pt 2):375-81
references: 12560570
references: Nature. 1998 Jan 1;391(6662):96-9
references: 9422513
references: Science. 1994 Dec 23;266(5193):2011-5
references: 7605428
references: Cancer Res. 1996 Feb 15;56(4):816-25
references: 8631019
references: J Neurosurg. 1994 Jun;80(6):1063-73
references: 7514661
references: J Biol Chem. 1995 Jun 16;270(24):14659-65
references: 7782328
references: Klin Padiatr. 1997 Jul-Aug;209(4):271-4
references: 9293461
references: Ann N Y Acad Sci. 1991;633:90-5
references: 1789597
references: Ann Intern Med. 1994 Oct 15;121(8):592-602
references: 8085692
references: Cancer. 2000 Dec 15;89(12):2661-6
references: 11135229
references: Mol Cell Biol. 1999 Dec;19(12 ):8469-78
references: 10567572
references: Proc Natl Acad Sci U S A. 1993 Jan 1;90(1):30-4
references: 8380496
references: J Biol Chem. 2002 Jul 26;277(30):27217-26
references: 12000759
references: Int J Oncol. 2005 Apr;26(4):1009-16
references: 15753996
references: Mutat Res. 2003 Feb-Mar;523-524:33-41
references: 12628501
references: Methods Enzymol. 1990;191:691-706
references: 1963657
references: J Biol Chem. 1985 Mar 25;260(6):3440-50
references: 3838314
references: J Neurosci Res. 2005 Aug 15;81(4):551-62
references: 15968645
references: Ann Oncol. 1994;5 Suppl 6:S3-6
references: 7865431
references: Cancer. 2001 Aug 1;92(3):519-23
references: 11505395
references: FEBS Lett. 2000 Jun 23;475(3):267-72
references: 10869569
references: Environ Health Perspect. 1999 Feb;107 Suppl 1:25-35
references: 10229704
references: Neurosurgery. 1995 Jan;36(1):1-21; discussion 21-2
references: 7708144
references: Annu Rev Immunol. 1997;15:563-91
references: 9143700
references: J Biol Chem. 1995 Feb 10;270(6):2497-505
references: 7852311
references: Brain Res. 1999 May 22;829(1-2):18-27
references: 10350526
references: Biochem Pharmacol. 2002 Jan 15;63(2):207-15
references: 11841795
references: Cancer Res. 2001 Feb 15;61(4):1477-85
references: 11245454
references: Int J Oncol. 2005 Oct;27(4):1013-21
references: 16142318
references: Proc Natl Acad Sci U S A. 1995 May 9;92(10):4507-11
references: 7753834
references: Arch Biochem Biophys. 1998 Aug 15;356(2):187-96
references: 9705209
references: Biochem J. 1996 Nov 1;319 ( Pt 3):683-90
references: 8920967
references: FEBS Lett. 2000 Sep 1;480(2-3):193-6
references: 11034327
references: Cancer Chemother Pharmacol. 2003 Aug;52(2):119-24
references: 12768320
references: Nature. 2000 Oct 12;407(6805):789-95
references: 11048730
references: Int J Cancer. 2003 Jan 1;103(1):53-60
references: 12455053
references: Cancer Res. 1997 Jan 1;57(1):130-5
references: 8988053
references: J Pharmacol Exp Ther. 1997 Dec;283(3):1177-84
references: 9399991
references: Br J Haematol. 2002 Jan;116(1):162-5
references: 11841411
references: J Biol Chem. 1997 Jun 27;272(26):16351-7
references: 9195941
references: J Biol Chem. 1998 Aug 28;273(35):22490-7
references: 9712874
references: Ann N Y Acad Sci. 2001 Jun;939:436-49
references: 11462799