title: ER stress sensitizes cells to TRAIL through down-regulation of FLIP and Mcl-1 and PERK-dependent up-regulation of TRAIL-R2.
abstract: Despite recent evidences suggesting that agents inducing endoplasmic reticulum (ER) stress could be exploited as potential antitumor drugs in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), the mechanisms of this anticancer action are not fully understood. Moreover, the effects of ER stress and TRAIL in nontransformed cells remain to be investigated. In this study we report that ER stress-inducing agents sensitizes both transformed and nontransformed cells to TRAIL-induced apoptosis. In addition, glucose-regulated protein of 78 kDa (GRP78) knockdown by RNA interference induces ER stress and facilitates apoptosis by TRAIL. We demonstrate that TRAIL death-inducing signaling complex (DISC) formation and early signaling are enhanced in ER stressed cells. ER stress alters the cellular levels of different apoptosis-related proteins including a decline in the levels of FLIP and Mcl-1 and the up-regulation of TRAIL-R2. Up-regulation of TRAIL-R2 following ER stress is dependent on the expression of PKR-like ER kinase (PERK) and independent of CAAT/enhancer binding protein homologous protein (CHOP) and Ire1α. Silencing of TRAIL-R2 expression by siRNA blocks the ER stress-mediated sensitization to TRAIL-induced apoptosis. Furthermore, simultaneous silencing of cFLIP and Mcl-1 expression by RNA interference results in a marked sensitization to TRAIL-induced apoptosis. Finally, in FLIP-overexpressing cells ER stress-induced sensitization to TRAIL-activated apoptosis is markedly reduced. In summary, our data reveal a pleiotropic mechanism involving both apoptotic and anti-apoptotic proteins for the sensitizing effect of ER stress on the regulation of TRAIL receptor-mediated apoptosis in both transformed and nontransformed cells.
authors.affiliation: Centro Andaluz de Biología Molecular y Medicina Regenerativa, Consejo Superior de Investigaciones Científicas, Sevilla, Spain.
authors.forename: Rosa
authors.initials: R
authors.lastname: Martín-Pérez
authors.forename: Maho
authors.initials: M
authors.lastname: Niwa
authors.forename: Abelardo
authors.initials: A
authors.lastname: López-Rivas
mesh_terms: D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics* / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*; D056811:Unfolded Protein Response; D015854:Up-Regulation; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D000091342:Endoplasmic Reticulum Chaperone BiP; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; D019892:eIF-2 Kinase; C000717247:HSPA5 protein, human; C505639:TNFRSF10B protein, human
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 12;105(32):11317-22
references.pmid: 18685088
references.citation: J Biol Chem. 2001 Jun 8;276(23):20633-40
references.pmid: 11279218
references.citation: Oncogene. 2003 Nov 24;22(53):8628-33
references.pmid: 14634624
references.citation: Cell. 2009 Jul 23;138(2):377-88
references.pmid: 19632185
references.citation: Nat Med. 1999 Feb;5(2):157-63
references.pmid: 9930862
references.citation: Cancer Cell. 2007 Jul;12(1):66-80
references.pmid: 17613437
references.citation: Cell Death Differ. 2010 May;17(5):883-94
references.pmid: 19942932
references.citation: Cell. 2006 Feb 10;124(3):601-13
references.pmid: 16469705
references.citation: J Biol Chem. 2004 Aug 20;279(34):35829-39
references.pmid: 15155747
references.citation: Cancer Res. 2006 Sep 1;66(17):8858-69
references.pmid: 16951203
references.citation: Cancer Res. 2008 Sep 15;68(18):7484-92
references.pmid: 18794136
references.citation: Mol Cell Biol. 2003 Feb;23(4):1278-91
references.pmid: 12556488
references.citation: J Biol Chem. 2006 May 12;281(19):13694-13707
references.pmid: 16543232
references.citation: Cancer Res. 2000 Jun 1;60(11):3051-7
references.pmid: 10850456
references.citation: Cell Death Differ. 2004 Apr;11(4):372-80
references.pmid: 14765132
references.citation: PLoS One. 2010 Jul 29;5(7):e11865
references.pmid: 20686688
references.citation: J Biol Chem. 2004 Oct 29;279(44):45495-502
references.pmid: 15322075
references.citation: Cancer Res. 2007 Jun 15;67(12):5880-8
references.pmid: 17575157
references.citation: Science. 2000 Jan 28;287(5453):664-6
references.pmid: 10650002
references.citation: Genes Dev. 1998 Apr 1;12(7):982-95
references.pmid: 9531536
references.citation: J Biol Chem. 2003 Nov 7;278(45):44338-47
references.pmid: 12920112
references.citation: Oncogene. 2002 Apr 18;21(17):2623-33
references.pmid: 11965535
references.citation: J Biol Chem. 2002 Jun 21;277(25):22320-9
references.pmid: 11940602
references.citation: Nature. 1988 Mar 31;332(6163):462-4
references.pmid: 3352747
references.citation: Cancer Res. 2007 Nov 15;67(22):10631-4
references.pmid: 18006802
references.citation: Mol Cell Biol. 1996 Apr;16(4):1479-89
references.pmid: 8657121
references.citation: Mol Cell. 2003 Mar;11(3):619-33
references.pmid: 12667446
references.citation: Immunity. 2000 Jun;12(6):599-609
references.pmid: 10894160
references.citation: J Clin Invest. 1999 Jul;104(2):155-62
references.pmid: 10411544
references.citation: J Biol Chem. 2002 Nov 15;277(46):43730-4
references.pmid: 12223490
references.citation: Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1754-9
references.pmid: 10677530
references.citation: Nat Rev Drug Discov. 2008 Dec;7(12):1001-12
references.pmid: 18989337
references.citation: Nat Cell Biol. 2000 Jun;2(6):326-32
references.pmid: 10854322
references.citation: J Biol Chem. 2005 May 13;280(19):19401-9
references.pmid: 15760909
references.citation: Cell. 2005 Jul 1;121(7):1085-95
references.pmid: 15989957
references.citation: Genes Dev. 2003 Jun 15;17(12):1475-86
references.pmid: 12783855
references.citation: Anal Biochem. 1994 May 1;218(2):314-9
references.pmid: 8074286
references.citation: Genes Dev. 2002 Jan 1;16(1):33-45
references.pmid: 11782443
references.citation: Immunity. 2000 Jun;12(6):633-42
references.pmid: 10894163
references.citation: Cancer Res. 2005 Jul 15;65(14):6364-70
references.pmid: 16024639
references.citation: Cancer Res. 1999 Feb 1;59(3):734-41
references.pmid: 9973225
references.citation: J Biol Chem. 2005 Jul 22;280(29):27345-55
references.pmid: 15886205
references.citation: Mol Cancer. 2009 Dec 14;8:122
references.pmid: 20003459
references.citation: Nature. 1997 Jul 10;388(6638):190-5
references.pmid: 9217161
references.citation: Immunity. 2000 Jun;12(6):611-20
references.pmid: 10894161
references.citation: J Biol Chem. 2007 Oct 12;282(41):29831-46
references.pmid: 17698840
references.citation: J Biol Chem. 2007 May 11;282(19):14132-9
references.pmid: 17371867
references.citation: Oncogene. 2001 Oct 25;20(48):7128-33
references.pmid: 11704839
references.citation: Mol Biol Cell. 2006 Jul;17(7):3095-107
references.pmid: 16672378
references.citation: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references.pmid: 17565364
references.citation: J Toxicol Sci. 2006 May;31(2):149-56
references.pmid: 16772704
references.citation: Nature. 2002 Jan 3;415(6867):92-6
references.pmid: 11780124
references.citation: Mol Cell. 2009 Sep 11;35(5):551-61
references.pmid: 19748352
references.citation: Blood. 2011 Jan 27;117(4):1311-4
references.pmid: 21081713
references.citation: Cell Death Differ. 2006 Aug;13(8):1260-2
references.pmid: 16710358