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

Abstract

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-␣) 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.

Association of Shiga toxin glycosphingolipid receptors with membrane microdomains of toxin-sensitive lymphoid and myeloid cells

“…Gb3Cer-and Gb4Cer-negative Jurkat and HL-60 cell lines were resistant, whereas Raji (Gb3Cer-positive) and THP-1 cells (Gb3Cer-and Gb4Cer-positive) were susceptible to Stx2, as expected from toxin treatment studies of THP-1 cells performed by others (98)(99)(100). However, THP-1 cells exhibited a rather moderate but signifi cant susceptibility toward Stx2 when compared with resistant Jurkat and HL-60 cells, although a more pronounced cytotoxicity has been reported for THP-1 cells using Stx1 ( 101 ).…”

Novel Subtilase Cytotoxin Produced by Shiga-Toxigenic Escherichia coli Induces Apoptosis in Vero Cells via Mitochondrial Membrane Damage

“…The appearance was similar to that induced by tunicamycin (TM), an N-glycosylation inhibitor which causes ER stress, leading to apoptotic death in many cells. Stx1 also induces apoptosis (6,10,14), although bleb formation was not observed at this time point (Fig. 1).…”

Ouabain Protects against Shiga Toxin–Triggered Apoptosis by Reversing the Imbalance between Bax and Bcl-xL

“…It is well documented that Stx2 increases caspase-8 expression. 6,7 Caspase-8 may trigger a signaling cascade that results in caspase-3 cleavage and cell death without involving the mitochondrial pathway (the extrinsic apoptotic pathway), or it may act by stimulating the apoptotic oligomerizing factors Bax and Bak, which bind to the mitochondrial membrane and make it permeable. This leads to a series of events that also result in caspase-3 cleavage and cell death (the intrinsic apoptotic pathway).…”

“…This leads to a series of events that also result in caspase-3 cleavage and cell death (the intrinsic apoptotic pathway). 7 Bax belongs to the Bcl-2 family, which includes both pro-and antiapoptotic factors. Bcl-xL is an antiapoptotic member of the Bcl-2 family and a potent inhibitor of Bax.…”