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.
Shiga toxins (Stxs) induce apoptosis in a variety of cell types. Here, we show that Stx1 induces apoptosis in the undifferentiated myelogenous leukemia cell line THP-1 in the absence of tumor necrosis factor alpha (TNF-alpha) or death receptor (TNF receptor or Fas) expression. Caspase-8 and -3 inhibitors blocked, and caspase-6 and -9 inhibitors partially blocked, Stx1-induced apoptosis. Stx1 induced the mitochondrial pathway of apoptosis, as activation of caspase-8 triggered the (i) cleavage of Bid, (ii) disruption of mitochondrial membrane potential, and (iii) release of cytochrome c into the cytoplasm. Caspase-8, -9, and -3 cleavage and functional activities began 4 h after toxin exposure and peaked after 8 h of treatment. Caspase-6 may also contribute to Stx1-induced apoptosis by directly acting on caspase-8. It appears that functional Stx1 holotoxins must be transported to the endoplasmic reticulum to initiate apoptotic signaling through the ribotoxic stress response. These data suggest that Stxs may activate monocyte apoptosis via a novel caspase-8-dependent, death receptor-independent mechanism.
Lee
Sang-Yun
SY
Department of Medical Microbiology and Immunology, Room 407, Reynolds Medical Building, Texas A and M University System Health Science Center, College Station, TX 77843-1114, USA. syunlee@medicine.tamu.edu
Cherla
Rama P
RP
Caliskan
Isa
I
Tesh
Vernon L
VL
D017209:Apoptosis / Q000502:physiology*; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007951:Leukemia, Myeloid / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D022622:Shiga Toxin 1 / Q000378:metabolism*; D019014:fas Receptor
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; C491901:FAS protein, human; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D022622:Shiga Toxin 1; D019014:fas Receptor; C505407:CASP3 protein, human; C505514:CASP6 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053178:Caspase 6; D053181:Caspase 8; D020169:Caspases; D003546:Cysteine Endopeptidases