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PMID: 20515924 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Signaling through C/EBP homologous protein and death receptor 5 and calpain activation differentially regulate THP-1 cell maturation-dependent apoptosis induced by Shiga toxin type 1.

Infection and immunity ·Vol. 78 ·No. 8 ·2010-08-00 ·Pages 3378-91

Lee MS, Cherla RP, Lentz EK, Leyva-Illades D, Tesh VL

Abstract

Shiga toxins (Stxs) induce apoptosis via activation of the intrinsic and extrinsic pathways in many cell types. Toxin-mediated activation of the endoplasmic reticulum (ER) stress response was shown to be instrumental in initiating apoptosis in THP-1 myeloid leukemia cells. THP-1 cells responded to Shiga toxin type 1 (Stx1) in a cell maturation-dependent manner, undergoing rapid apoptosis in the undifferentiated state but reduced and delayed apoptosis in differentiated cells. The onset of apoptosis was associated with calpain activation and changes in expression of C/EBP homologous protein (CHOP), Bcl-2 family members, and death receptor 5 (DR5). Ligation of DR5 by tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) activates the extrinsic pathway of apoptosis. We show here that expression of TRAIL and DR5 is increased by Stx1 treatment. Addition of exogenous TRAIL enhances, and anti-TRAIL antibodies inhibit, Stx1-induced apoptosis of THP-1 cells. Silencing of CHOP or DR5 expression selectively prevented caspase activation, loss of mitochondrial membrane potential, and Stx1-induced apoptosis of macrophage-like THP-1 cells. In contrast, the rapid kinetics of apoptosis induction in monocytic THP-1 cells correlated with rates of calpain cleavage. The results suggest that CHOP-DR5 signaling and calpain activation differentially contribute to cell maturation-dependent Stx1-induced apoptosis. Inhibition of these signaling pathways may protect cells from Stx cytotoxicity.

MeSH Terms
Apoptosis Calpain/metabolism Cell Line Gene Silencing Humans Monocytes/drug effects,physiology Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism Shiga Toxin/toxicity Signal Transduction TNF-Related Apoptosis-Inducing Ligand/metabolism Transcription Factor CHOP/antagonists & inhibitors,metabolism
Chemicals
Receptors, TNF-Related Apoptosis-Inducing Ligand TNF-Related Apoptosis-Inducing Ligand TNFSF10 protein, human Transcription Factor CHOP Shiga Toxin Calpain
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Lee Moo-Seung
Department of Microbial and Molecular Pathogenesis, Texas A&M Health Science Center, College Station, TX 77843-1114, USA.
Cherla Rama P
Lentz Erin K
Leyva-Illades Dinorah
Tesh Vernon L
References (66)
66 references, click to expand
  1. Overexpression of BCL2 blocks TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in human lung cancer cells.
    Biochem Biophys Res Commun. 2001 Jan 26;280(3):788-97 PMID: 11162590
  2. Shiga toxin 1-induced proinflammatory cytokine production is regulated by the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin signaling pathway.
    Infect Immun. 2009 Sep;77(9):3919-31 PMID: 19596774
  3. Shiga toxin 1 induces apoptosis through the endoplasmic reticulum stress response in human monocytic cells.
    Cell Microbiol. 2008 Mar;10(3):770-80 PMID: 18005243
  4. Involvement of both mitochondrial- and death receptor-dependent apoptotic pathways regulated by Bcl-2 family in sodium fluoride-induced apoptosis of the human gingival fibroblasts.
    Toxicology. 2008 Jan 20;243(3):340-7 PMID: 18069112
  5. TRAIL-induced apoptosis: between tumor therapy and immunopathology.
    Ann N Y Acad Sci. 2009 Aug;1171:50-8 PMID: 19723037
  6. Crystal structure of the holotoxin from Shigella dysenteriae at 2.5 A resolution.
    Nat Struct Biol. 1994 Jan;1(1):59-64 PMID: 7656009
  7. Food-related illness and death in the United States.
    Emerg Infect Dis. 1999 Sep-Oct;5(5):607-25 PMID: 10511517
  8. Apo2L/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5.
    Immunity. 2000 Jun;12(6):611-20 PMID: 10894161
  9. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis.
    Cell. 1998 Aug 21;94(4):491-501 PMID: 9727492
  10. Apo2 ligand/TNF-related apoptosis-inducing ligand and death receptor 5 mediate the apoptotic signaling induced by ionizing radiation in leukemic cells.
    Cancer Res. 2000 Oct 15;60(20):5754-60 PMID: 11059770
  11. Overview of cell death signaling pathways.
    Cancer Biol Ther. 2005 Feb;4(2):139-63 PMID: 15725726
  12. Shiga toxin, Shiga-like toxin II variant, and ricin are all single-site RNA N-glycosidases of 28 S RNA when microinjected into Xenopus oocytes.
    J Biol Chem. 1989 Jan 5;264(1):596-601 PMID: 2642481
  13. Erythroid differentiation sensitizes K562 leukemia cells to TRAIL-induced apoptosis by downregulation of c-FLIP.
    Mol Cell Biol. 2003 Feb;23(4):1278-91 PMID: 12556488
  14. Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) up-regulates death receptor 5 (DR5) mediated by NFkappaB activation in epithelial derived cell lines.
    Apoptosis. 2002 Oct;7(5):413-20 PMID: 12207174
  15. Modulation of phagocyte apoptosis by bacterial pathogens.
    Apoptosis. 2004 Jul;9(4):399-413 PMID: 15192322
  16. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells.
    J Biol Chem. 2004 Oct 29;279(44):45495-502 PMID: 15322075
  17. Simultaneous induction of apoptotic and survival signaling pathways in macrophage-like THP-1 cells by Shiga toxin 1.
    Infect Immun. 2007 Mar;75(3):1291-302 PMID: 17194804
  18. FADD is required for DR4- and DR5-mediated apoptosis: lack of trail-induced apoptosis in FADD-deficient mouse embryonic fibroblasts.
    J Biol Chem. 2000 Aug 18;275(33):25065-8 PMID: 10862756
  19. Site of action of a Vero toxin (VT2) from Escherichia coli O157:H7 and of Shiga toxin on eukaryotic ribosomes. RNA N-glycosidase activity of the toxins.
    Eur J Biochem. 1988 Jan 15;171(1-2):45-50 PMID: 3276522
  20. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family.
    J Biol Chem. 1996 May 31;271(22):12687-90 PMID: 8663110
  21. Apoptotic pathways: paper wraps stone blunts scissors.
    Cell. 2000 Jul 7;102(1):1-4 PMID: 10929706
  22. Frequent mutations in the p53 gene in human myeloid leukemia cell lines.
    Blood. 1992 May 1;79(9):2378-83 PMID: 1571549
  23. Shiga toxin receptor glycolipid binding. Pathology and utility.
    Methods Mol Med. 2003;73:165-86 PMID: 12375428
  24. Apoptosis: a review of programmed cell death.
    Toxicol Pathol. 2007 Jun;35(4):495-516 PMID: 17562483
  25. Downregulation of Bcl-2, FLIP or IAPs (XIAP and survivin) by siRNAs sensitizes resistant melanoma cells to Apo2L/TRAIL-induced apoptosis.
    Cell Death Differ. 2004 Aug;11(8):915-23 PMID: 15118763
  26. Endoplasmic reticulum calcium pool depletion-induced apoptosis is coupled with activation of the death receptor 5 pathway.
    Oncogene. 2002 Apr 18;21(17):2623-33 PMID: 11965535
  27. Characterization of non-toxic mutant toxins of Vero toxin 1 that were constructed by replacing amino acids in the A subunit.
    Microb Pathog. 1993 Sep;15(3):169-76 PMID: 8271917
  28. Defining and assaying RNAi in mammalian cells.
    Mol Cell. 2005 Jan 7;17(1):1-10 PMID: 15629712
  29. An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis.
    J Biol Chem. 2002 Jun 21;277(25):22320-9 PMID: 11940602
  30. Escherichia coli shiga-like toxins induce apoptosis and cleavage of poly(ADP-ribose) polymerase via in vitro activation of caspases.
    Infect Immun. 2002 Aug;70(8):4669-77 PMID: 12117981
  31. Differential regulation of TRAIL and CD95 ligand in transformed cells of the T and B lymphocyte lineage.
    Eur J Immunol. 1998 Mar;28(3):973-82 PMID: 9541592
  32. TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB.
    Immunity. 1997 Dec;7(6):831-6 PMID: 9430228
  33. Use of an aqueous soluble tetrazolium/formazan assay for cell growth assays in culture.
    Cancer Commun. 1991 Jul;3(7):207-12 PMID: 1867954
  34. Shiga toxin type 1 activates tumor necrosis factor-alpha gene transcription and nuclear translocation of the transcriptional activators nuclear factor-kappaB and activator protein-1.
    Blood. 1998 Jul 15;92(2):558-66 PMID: 9657756
  35. Calpain activation is upstream of caspases in radiation-induced apoptosis.
    Cell Death Differ. 1998 Dec;5(12):1051-61 PMID: 9894612
  36. A unique zinc-binding site revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL.
    Biochemistry. 2000 Feb 1;39(4):633-40 PMID: 10651627
  37. The treatment of malignant meningioma with verotoxin.
    Neoplasia. 2002 Jul-Aug;4(4):304-11 PMID: 12082546
  38. Comparison of the relative toxicities of Shiga-like toxins type I and type II for mice.
    Infect Immun. 1993 Aug;61(8):3392-402 PMID: 8335369
  39. X-linked inhibitor of apoptosis protein (XIAP) is a nonredundant modulator of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human cancer cells.
    Cancer Res. 2004 May 1;64(9):3006-8 PMID: 15126334
  40. Staying alive: bacterial inhibition of apoptosis during infection.
    Trends Microbiol. 2008 Apr;16(4):173-80 PMID: 18353648
  41. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway signaling.
    J Thorac Oncol. 2007 Jun;2(6):461-5 PMID: 17545839
  42. Expression of verotoxin-1 receptor Gb3 in breast cancer tissue and verotoxin-1 signal transduction to apoptosis.
    BMC Cancer. 2009 Feb 26;9:67 PMID: 19245689
  43. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome.
    Lancet. 2005 Mar 19-25;365(9464):1073-86 PMID: 15781103
  44. Synergistic activation of caspase-3 by m-calpain after neonatal hypoxia-ischemia: a mechanism of "pathological apoptosis"?
    J Biol Chem. 2001 Mar 30;276(13):10191-8 PMID: 11124942
  45. TRAIL as a target in anti-cancer therapy.
    Cancer Lett. 2009 Nov 18;285(1):1-5 PMID: 19299078
  46. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages.
    J Immunol. 1992 Apr 1;148(7):2207-16 PMID: 1545126
  47. Shiga toxins and apoptosis.
    FEMS Microbiol Lett. 2003 Nov 21;228(2):159-66 PMID: 14638419
  48. Differentiation-associated toxin receptor modulation, cytokine production, and sensitivity to Shiga-like toxins in human monocytes and monocytic cell lines.
    Infect Immun. 1996 Apr;64(4):1173-80 PMID: 8606075
  49. Two toxin-converting phages from Escherichia coli O157:H7 strain 933 encode antigenically distinct toxins with similar biologic activities.
    Infect Immun. 1986 Jul;53(1):135-40 PMID: 3522426
  50. The role of BH3-only proteins in the immune system.
    Nat Rev Immunol. 2005 Mar;5(3):189-200 PMID: 15719025
  51. Death receptors as targets of cancer therapeutics.
    Curr Cancer Drug Targets. 2004 Feb;4(1):97-104 PMID: 14965271
  52. Isolation and molecular characterization of the 5'-upstream region of the human TRAIL gene.
    Biochem Biophys Res Commun. 2000 Sep 24;276(2):466-71 PMID: 11027498
  53. Rapid apoptosis induced by Shiga toxin in HeLa cells.
    Infect Immun. 2003 May;71(5):2724-35 PMID: 12704147
  54. Bcl-2 regulates the onset of shiga toxin 1-induced apoptosis in THP-1 cells.
    Infect Immun. 2009 Dec;77(12):5233-44 PMID: 19752028
  55. Death receptors: signaling and modulation.
    Science. 1998 Aug 28;281(5381):1305-8 PMID: 9721089
  56. Shiga toxins.
    Toxicon. 2001 Nov;39(11):1629-35 PMID: 11595626
  57. Shiga toxin 1-induced activation of c-Jun NH(2)-terminal kinase and p38 in the human monocytic cell line THP-1: possible involvement in the production of TNF-alpha.
    J Leukoc Biol. 2002 Jan;71(1):107-14 PMID: 11781386
  58. Comparative evaluation of apoptosis induced by Shiga toxin 1 and/or lipopolysaccharides in human monocytic and macrophage-like cells.
    Microb Pathog. 2005 Feb-Mar;38(2-3):63-76 PMID: 15748808
  59. Shiga toxin 1 induces apoptosis in the human myelogenous leukemia cell line THP-1 by a caspase-8-dependent, tumor necrosis factor receptor-independent mechanism.
    Infect Immun. 2005 Aug;73(8):5115-26 PMID: 16041028
  60. Shiga-like toxin inhibition of FLICE-like inhibitory protein expression sensitizes endothelial cells to bacterial lipopolysaccharide-induced apoptosis.
    J Biol Chem. 2002 Oct 25;277(43):40567-74 PMID: 12189147
  61. Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL.
    J Biol Chem. 1997 Oct 10;272(41):25417-20 PMID: 9325248
  62. Identification and characterization of a new member of the TNF family that induces apoptosis.
    Immunity. 1995 Dec;3(6):673-82 PMID: 8777713
  63. Caspase-8 in cancer biology and therapy.
    Cancer Lett. 2009 Aug 28;281(2):128-33 PMID: 19111387
  64. 15-deoxy-Delta12,14-prostaglandin J2 up-regulates death receptor 5 gene expression in HCT116 cells: involvement of reactive oxygen species and C/EBP homologous transcription factor gene transcription.
    Mol Cancer Ther. 2008 Oct;7(10):3429-40 PMID: 18852146
  65. Characterization of the baboon responses to Shiga-like toxin: descriptive study of a new primate model of toxic responses to Stx-1.
    Am J Pathol. 1999 Apr;154(4):1285-99 PMID: 10233866
  66. TRAIL resistance results in cancer progression: a TRAIL to perdition?
    Oncogene. 2006 Nov 30;25(56):7333-5 PMID: 16785986
Article Info
Journal
Infection and immunity
Abbr.
Infect Immun
ISSN
1098-5522
DOI
10.1128/IAI.00342-10
Published
2010-08-00
Epub
2010-00-01
Pages
3378-91
Language
English
Region
United States
NLM ID
0246127
PMCID
PMC2916263
Subset
IM
Grants
NIAID NIH HHS · R01 AI034530 · United States
NIAID NIH HHS · R01 AI34530 · United States
External Links
PubMed source DOI: 10.1128/IAI.00342-10 PMC Full Text View journal details
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