<i>Clostridium difficile</i>Toxin B Induces Apoptosis in Intestinal Cultured Cells

Fiorentini, Carla; Fabbri, Alessia; Falzano, Loredana; Fattorossi, Andrea; Matarrese, Paola; Rivabene, Roberto; Donelli, Gianfranco

doi:10.1128/iai.66.6.2660-2665.1998

Cited by 91 publications

(35 citation statements)

References 38 publications

(35 reference statements)

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“…14 %), and the occurrence of apoptosis was further confirmed by ladders of DNA fragmentation. These results are in agreement with previous observations in breast-cancer cells and intestinal cultured cells [30,32]. However, studies in human endothelial cells have showed that inactivation of Cdc42 and Rac cannot influence apoptosis, but their inhibition reduces the expression of the anti-apoptotic genes Bcl-2 and Mcl-1 and increases the expression of pro-apoptotic Bid [33].…”

Section: Discussionsupporting

confidence: 92%

RNA‐interference‐mediated Cdc42 silencing down‐regulates phosphorylation of STAT3 and suppresses growth in human bladder‐cancer cells

Chen

Li³

et al. 2008

Biotech and App Biochem

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Cdc42 (cell division cycle 42), a member of Rho GTPases, is involved in cell transformation, proliferation, survival, invasion and metastasis of human cancer cells. Here, RNAi (RNA interference)-mediated gene silencing was used to investigate the roles of Cdc42 and to assess its therapeutic potential in human bladder cancer. The results showed that Cdc42 silencing resulted in a marked reduction of Cdc42 mRNA and protein expression and a significant inhibition of cell proliferation from G(0)/G(1)- to S-phase in two (EJ and T24) human bladder-cancer cell lines. Moreover, RNAi-mediated inhibition of Cdc42 induced apoptosis of EJ cells 96 h after transfection. In addition, we found that silencing of Cdc42 could down-regulate the level of phosphorylated STAT3 (signal transducer and activator of transcription 3), but did not influence the level of total STAT3 in the two bladder-cancer cell lines. These results suggest that RNAi-mediated Cdc42 silencing may be a novel approach for gene therapy of bladder cancer.

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Section: Discussionsupporting

confidence: 92%

RNA‐interference‐mediated Cdc42 silencing down‐regulates phosphorylation of STAT3 and suppresses growth in human bladder‐cancer cells

Chen

Li³

et al. 2008

Biotech and App Biochem

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“…PI staining also occurs at early time‐points and suggests some cells from this population could be going through necrotic cell death or late apoptosis. These results may explain earlier conflicting reports regarding cell necrosis vs. apoptosis in TcdB‐intoxicated cells (Warny and Kelly, 1999; Fiorentini et al. , 1998).…”

Section: Discussionmentioning

confidence: 51%

“…, 2000) reported PARP cleavage in cells treated with TcdB, further suggesting caspase activation during TcdB induced apoptosis. Interestingly, Warny and Kelly (1999) reported finding necrotic cell death in TcdB‐treated THP‐1 monocytes, while Fiorentini et al. (1998) reported that TcdB was a potent inducer of apoptosis in IEC‐6 intestinal cells.…”

Section: Introductionmentioning

confidence: 99%

Clostridium difficile toxin B activates dual caspase-dependent and caspase-independent apoptosis in intoxicated cells

Qa'Dan

Ramsey²,

Daniel³

et al. 2002

Cell Microbiol

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SummaryClostridium difficile toxin B (TcdB) inactivates the small GTPases Rho, Rac and Cdc42 during intoxication of mammalian cells. In the current work, we show that TcdB has the potential to stimulate caspase-dependent and caspase-independent apoptosis. The apoptotic pathways became evident when caspase-3-processed-vimentin was detected in TcdBtreated HeLa cells. Caspase-3 activation was subsequently confirmed in TcdB-intoxicated HeLa cells. Interestingly, caspase inhibitor delayed TcdB-induced cell death, but did not alter the time-course of cytopathic effects. A similar effect was also observed in MCF-7 cells, which are deficient in caspase-3 activity. The time-course to cell death was almost identical between cells treated with TcdB plus caspase inhibitor and cells intoxicated with the TcdB enzymatic domain (TcdB 1-556 ). Unlike TcdB treated cells, intoxication with TcdB 1-556 or expression of TcdB 1-556 in a transfected cell line, did not stimulate caspase-3 activation yet cells exhibited cytopathic effects and cell death. Although TcdB 1-556 treated cells did not demonstrate caspase-3 activation these cells were apoptotic as determined by differential annexin-V/propidium iodide staining and nucleosomal DNA fragmentation. These data indicate TcdB triggers caspase-independent apoptosis as a result of substrate inactivation and may evoke caspasedependent apoptosis due to a second, yet undefined, activity of TcdB. This is the first example of a bacterial virulence factor with the potential to stimulate multiple apoptotic pathways in host cells.

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“…Staphylococcus aureus does not require internalization to be toxic as its α‐toxin which induces pore formation is responsible for the bacteria cytotoxicity. Among the bacterial toxins known to inhibit small GTPases, toxins A and B of Clostridium difficile have been shown to induce apoptosis in intestinal cultured cells (Fiorentini et al ., 1998; Brito et al ., 2002) as well as other cell types (Linseman et al ., 2001; Hippenstiel et al ., 2002). The level of apoptotic signalling initiation has not been clearly established in these studies but apoptotic cell death was mostly interpreted as a direct consequence of Rho GTPases modification.…”

Section: Discussionmentioning

confidence: 99%

Lethal toxin fromClostridium sordelliiinduces apoptotic cell death by disruption of mitochondrial homeostasis in HL-60 cells

Petit

Bréard

Montalescot

et al. 2003

Cellular Microbiology

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SummaryLethal toxin (LT) from Clostridium sordellii (strain IP82) inactivates in glucosylating the small GTPases Ras, Rap, Ral and Rac. In the present study we show that LT-IP82 induces cell death via an intrinsic apoptotic pathway in the myeloid cell-line HL-60. LT-IP82 was found to disrupt mitochondrial homeostasis as characterized by a decrease in mitochondrial transmembrane potential and cardiolipin alterations, associated with the release of cytochrome c in the cytosol. Time-course studies of caspase activation revealed that caspase-9 and caspase-3 were activated before caspase-8. Moreover, although LT-IP82-induced cell death was abrogated by caspase-inhibitors, these inhibitors did not suppress mitochondrial alterations, indicating that caspase activation occurs downstream of mitochondria. Protection of mitochondria by Bcl-2 overexpression prevented mitochondrial changes as well as apoptosis induction. Furthermore, evidence is provided that LT-IP82-induced apoptosis is not a consequence of cortical actin disorganization, suggesting that Rac inactivation does not initiate the apoptotic process. Cell exposure to LT-IP82 leads to a co-localization of the toxin with a mitochondrial marker within 2 h. Therefore, we suggest that LT-IP82 could act at the mitochondrion level independently of its enzymatic effect on small GTPases.

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Clostridium difficileToxin B Induces Apoptosis in Intestinal Cultured Cells

Cited by 91 publications

References 38 publications

RNA‐interference‐mediated Cdc42 silencing down‐regulates phosphorylation of STAT3 and suppresses growth in human bladder‐cancer cells

RNA‐interference‐mediated Cdc42 silencing down‐regulates phosphorylation of STAT3 and suppresses growth in human bladder‐cancer cells

Clostridium difficile toxin B activates dual caspase-dependent and caspase-independent apoptosis in intoxicated cells

Lethal toxin fromClostridium sordelliiinduces apoptotic cell death by disruption of mitochondrial homeostasis in HL-60 cells

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