title: Caspase inhibition blocks cell death and enhances mitophagy but fails to promote T-cell lymphoma.
abstract: Caspase-9 is a component of the apoptosome that mediates cell death following release of cytochrome c from mitochondria. Inhibition of Caspase-9 with a dominant negative construct (Casp9DN) blocks apoptosome function, promotes viability and has been implicated in carcinogenesis. Inhibition of the apoptosome in vitro impairs mitochondrial function and promotes mitophagy. To examine whether inhibition of the apoptosome would enhance mitophagy and promote oncogenesis in vivo, transgenic mice were generated that express Casp9DN in the T cell lineage. The effects of Casp9DN on thymocyte viability, mitophagy and thymic tumor formation were examined. In primary thymocytes, Casp9DN delayed dexamethasone (Dex)-induced cell death, altered mitochondrial structure, and decreased oxidant production. Transmission electron microscopy (TEM) revealed that inhibition of the apoptosome resulted in structurally abnormal mitochondria that in some cases were engulfed by double-membrane structures resembling autophagosomes. Consistent with mitochondria being engulfed by autophagosomes (mitophagy), confocal microscopy showed colocalization of LC3-GFP and mitochondria. However, Casp9DN did not significantly accelerate T-cell lymphoma alone, or in combination with Lck-Bax38/1, or with Beclin 1+/- mice, two tumor-prone strains in which altered mitochondrial function has been implicated in promoting tumor development. In addition, heterozygous disruption of Beclin 1 had no effect on T-cell lymphoma formation in Lck-Bax38/1 mice. Further studies showed that Beclin 1 levels had no effect on Casp9DN-induced loss of mitochondrial function. These results demonstrate that neither inhibition of apoptosome function nor Beclin 1 haploinsufficiency accelerate T-cell lymphoma development in mice.
authors: Department of Pathology, Roy J. and Lucille P. Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America.
authors: Sih-han
authors: SH
authors: Wang
authors: Sean M
authors: SM
authors: Martin
authors: Peter S
authors: PS
authors: Harris
authors: C Michael
authors: CM
authors: Knudson
references: J Cell Biol. 1996 Dec;135(5):1341-54
references: 8947555
references: Cancer Cell. 2002 Apr;1(3):289-98
references: 12086865
references: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15077-82
references: 14657337
references: Cancer Res. 1998 Mar 1;58(5):997-1003
references: 9500462
references: Cancer Res. 2001 Jan 15;61(2):659-65
references: 11212265
references: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):6164-9
references: 15079075
references: Mol Cell. 2008 Jun 20;30(6):678-88
references: 18570871
references: Int J Cancer. 2010 Aug 15;127(4):873-80
references: 20013803
references: Cell. 1998 Aug 7;94(3):325-37
references: 9708735
references: J Clin Invest. 2003 Dec;112(12):1809-20
references: 14638851
references: Science. 1997 Feb 14;275(5302):967-9
references: 9020077
references: Dig Liver Dis. 2008 Jul;40(7):599-600
references: 18373966
references: J Clin Invest. 1998 May 1;101(9):1992-9
references: 9576764
references: Genes Dev. 2007 Jul 1;21(13):1621-35
references: 17606641
references: Cell. 1989 Apr 7;57(1):79-88
references: 2649247
references: Clin Cancer Res. 2001 Aug;7(8):2468-74
references: 11489828
references: Science. 1999 Apr 2;284(5411):156-9
references: 10102818
references: Genes Dev. 2007 Jun 1;21(11):1367-81
references: 17510285
references: Oncogene. 2007 Feb 26;26(9):1324-37
references: 17322918
references: PLoS One. 2008 Apr 02;3(4):e1911
references: 18382684
references: Biochem Biophys Res Commun. 2007 Jun 22;358(1):203-8
references: 17475217
references: Free Radic Biol Med. 2008 Apr 15;44(8):1677-86
references: 18291119
references: Cell. 2007 Jun 1;129(5):983-97
references: 17540177
references: Clin Cancer Res. 2003 Oct 15;9(13):4914-25
references: 14581366
references: Clin Cancer Res. 2000 May;6(5):1796-803
references: 10815900
references: J Cell Biol. 2004 Jan 5;164(1):89-96
references: 14709542
references: Cell. 2005 Sep 23;122(6):927-39
references: 16179260
references: Dev Cell. 2010 May 18;18(5):802-13
references: 20493813
references: Eur J Cancer. 2001 Nov;37(17):2217-21
references: 11677110
references: Genomics. 1999 Jul 1;59(1):59-65
references: 10395800
references: J Biol Chem. 2007 Jan 26;282(4):2144-55
references: 17102131
references: Cell Death Differ. 2003 Jun;10(6):740-8
references: 12761582
references: APMIS. 2006 Apr;114(4):292-7
references: 16689829
references: Mol Cancer Res. 2005 Jun;3(6):325-34
references: 15972851
references: Cell. 2009 Jun 12;137(6):1062-75
references: 19524509
references: Nature. 2001 Jan 11;409(6817):207-11
references: 11196646
references: Cell. 2005 Jan 28;120(2):237-48
references: 15680329
references: Exp Neurol. 2000 Jan;161(1):203-11
references: 10683286
references: Clin Cancer Res. 2010 Jan 15;16(2):509-20
references: 20068072
references: Oncogene. 1998 Apr 9;16(14):1803-12
references: 9583678
references: Cell. 1985 Jul;41(3):899-906
references: 3924412