title: ATM-NFκB axis-driven TIGAR regulates sensitivity of glioma cells to radiomimetics in the presence of TNFα.
abstract: Gliomas are resistant to radiation therapy, as well as to TNFα induced killing. Radiation-induced TNFα triggers Nuclear factor κB (NFκB)-mediated radioresistance. As inhibition of NFκB activation sensitizes glioma cells to TNFα-induced apoptosis, we investigated whether TNFα modulates the responsiveness of glioma cells to ionizing radiation-mimetic Neocarzinostatin (NCS). TNFα enhanced the ability of NCS to induce glioma cell apoptosis. NCS-mediated death involved caspase-9 activation, reduction of mitochondrial copy number and lactate production. Death was concurrent with NFκB, Akt and Erk activation. Abrogation of Akt and NFκB activation further potentiated the death inducing ability of NCS in TNFα cotreated cells. NCS-induced p53 expression was accompanied by increase in TP53-induced glycolysis and apoptosis regulator (TIGAR) levels and ATM phosphorylation. siRNA-mediated knockdown of TIGAR abrogated NCS-induced apoptosis. While DN-IκB abrogated NCS-induced TIGAR both in the presence and absence of TNFα, TIGAR had no effect on NFκB activation. Transfection with TIGAR mutant (i) decreased apoptosis and γH2AX foci formation (ii) decreased p53 (iii) elevated ROS and (iv) increased Akt/Erk activation in cells cotreated with NCS and TNFα. Heightened TIGAR expression was observed in GBM tumors. While NCS induced ATM phosphorylation in a NFκB independent manner, ATM inhibition abrogated TIGAR and NFκB activation. Metabolic gene profiling indicated that TNFα affects NCS-mediated regulation of several genes associated with glycolysis. The existence of ATM-NFκB axis that regulate metabolic modeler TIGAR to overcome prosurvival response in NCS and TNFα cotreated cells, suggests mechanisms through which inflammation could affect resistance and adaptation to radiomimetics despite concurrent induction of death.
authors: Cellular and Molecular Neuroscience Division, National Brain Research Centre, Manesar, Haryana, India.
authors: S
authors: S
authors: Sinha
authors: R
authors: R
authors: Ghildiyal
authors: V S
authors: VS
authors: Mehta
authors: E
authors: E
authors: Sen
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D053453:Caspase 9 / Q000737:chemistry / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism / Q000473:pathology; D006019:Glycolysis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D009353:Zinostatin / Q000494:pharmacology*
chemical_list: D000903:Antibiotics, Antineoplastic; D051017:Apoptosis Regulatory Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D019344:Lactic Acid; D000255:Adenosine Triphosphate; D009353:Zinostatin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human; D053453:Caspase 9
references: Cancer Res. 2004 Sep 1;64(17):6233-9
references: 15342409
references: Mol Cell Biol. 2008 Nov;28(21):6632-45
references: 18779315
references: J Mol Med (Berl). 2012 Jan;90(1):67-80
references: 21887505
references: Cell Death Dis. 2012 Feb 09;3:e271
references: 22318540
references: J Exp Med. 2011 Feb 14;208(2):313-26
references: 21242296
references: Oncogene. 2001 Apr 26;20(18):2243-53
references: 11402319
references: J Biol Chem. 2012 Sep 28;287(40):33436-46
references: 22887998
references: Cell Death Dis. 2012 Jan 19;3:e258
references: 22258408
references: Free Radic Biol Med. 2009 Jun 1;46(11):1543-50
references: 19324081
references: Nature. 2006 Dec 7;444(7120):756-60
references: 17051156
references: Science. 2006 Feb 24;311(5764):1141-6
references: 16497931
references: J Biol Chem. 2010 Mar 5;285(10):7324-33
references: 20018866
references: Mol Cell Biol. 2000 Mar;20(5):1626-38
references: 10669740
references: Science. 1996 Nov 1;274(5288):782-4
references: 8864118
references: Science. 1997 Feb 21;275(5303):1132-6
references: 9027315
references: J Mol Med (Berl). 2011 Feb;89(2):123-36
references: 20865400
references: PLoS One. 2008 Feb 06;3(2):e1550
references: 18253497
references: Mol Cancer Ther. 2007 Sep;6(9):2544-53
references: 17876051
references: J Hepatol. 2011 Jan;54(1):164-72
references: 20961644
references: J Clin Invest. 1991 Aug;88(2):691-5
references: 1864978
references: Nat Cell Biol. 2011 Aug 28;13(10):1272-9
references: 21968997
references: Oncotarget. 2010 Nov;1(7):552-62
references: 21317451
references: Trends Biochem Sci. 2012 Aug;37(8):317-24
references: 22626470
references: J Cell Biol. 2006 Dec 18;175(6):913-23
references: 17158952
references: J Biol Chem. 2003 Jan 31;278(5):2963-8
references: 12433922
references: Free Radic Biol Med. 2009 Aug 15;47(4):364-74
references: 19409983
references: Mol Cancer Res. 2008 Jan;6(1):78-88
references: 18234964
references: Science. 1996 Nov 1;274(5288):784-7
references: 8864119
references: Nat Cell Biol. 2008 May;10(5):611-8
references: 18391940
references: EMBO J. 2011 Feb 2;30(3):546-55
references: 21157431
references: Cell Death Dis. 2012 Jan 12;3:e249
references: 22237206
references: J Biol Chem. 2005 Apr 1;280(13):12593-601
references: 15642734
references: Free Radic Biol Med. 1998 May;24(7-8):1256-68
references: 9626582
references: Cell Cycle. 2011 Feb 1;10(3):481-91
references: 21263216
references: Genes Dev. 2008 Jun 15;22(12):1577-90
references: 18559474
references: Radiother Oncol. 2010 Jan;94(1):102-9
references: 20036432
references: Oncogene. 2002 Jan 24;21(5):849-55
references: 11850813
references: Mol Carcinog. 2013 Dec;52(12):970-82
references: 22753156
references: Oncogene. 2006 Aug 7;25(34):4633-46
references: 16892078
references: J Biol Chem. 2005 Feb 11;280(6):4029-36
references: 15546863
references: J Biol Chem. 2011 Jun 17;286(24):21588-600
references: 21527635
references: Cell Cycle. 2012 Mar 15;11(6):1167-73
references: 22370485
references: Carcinogenesis. 2013 Feb;34(2):388-96
references: 23125226
references: Mol Cell Biol. 2001 Sep;21(17):5899-912
references: 11486029
references: J Clin Invest. 2007 Sep;117(9):2723-34
references: 17786248
references: Oncogene. 2001 Oct 4;20(45):6570-8
references: 11641782
references: Proc Natl Acad Sci U S A. 1985 Nov;82(22):7626-30
references: 2999773
references: Cell Death Differ. 2007 Mar;14(3):548-58
references: 16946731
references: Nat Med. 2005 Dec;11(12):1306-13
references: 16286925
references: Mutat Res. 2004 Dec 2;568(1):97-110
references: 15530543
references: Radiother Oncol. 2011 Oct;101(1):132-9
references: 21864926
references: EMBO J. 2009 Oct 7;28(19):3015-26
references: 19713938
references: Cell. 2006 Jul 14;126(1):107-20
references: 16839880
references: J Biol Chem. 2001 Nov 9;276(45):42462-7
references: 11571274
references: Oncogene. 1999 Apr 1;18(13):2261-71
references: 10327072
references: J Biol Chem. 1998 Mar 6;273(10):5858-68
references: 9488723