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Infection and Immunity, December 2009, p. 5400-5410, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00485-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Antiapoptotic Proteins Bcl-2 and Bcl-XL Inhibit Clostridium difficile Toxin A-Induced Cell Death in Human Epithelial Cells {triangledown}

Isabelle Matte, Denis Lane, Élodie Côté, Ann-Élise Asselin, Louis-Charles Fortier, Claude Asselin, and Alain Piché*

Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbooke, Canada J1H 5N4

Received 1 May 2009/ Returned for modification 3 August 2009/ Accepted 16 September 2009

It has been well established that Clostridium difficile toxin A (TcdA) induces cell death in human epithelial cells. However, the mechanism of TcdA-induced cell death remains to be fully characterized. Here, we show that TcdA induces dose-dependent cell death in ovarian carcinoma and colonic carcinoma cell lines. TcdA-mediated cell death, as well as caspase 8 and caspase 3 activation, were specifically abrogated by anti-toxin antibodies. Although caspase 8 and caspase 3 were activated by TcdA in OVCAR3 ovarian carcinoma and T84 colonic cancer cells, pancaspase and caspase 8, 3, and 9 inhibitors did not block TcdA-induced cell death. In contrast, tumor necrosis factor-related apoptosis-inducing ligand-induced cell death was nearly completely blocked by caspase inhibitors in OVCAR3 cells. In these cells, TcdA induces the mitochondrial pathway of apoptosis, as demonstrated by changes in mitochondrial outer membrane permeabilization (MOMP). Furthermore, overexpression of the antiapoptotic proteins Bcl-2 and Bcl-XL significantly inhibited TcdA-induced cell death, as well as TcdA-induced MOMP. Conversely, small interfering RNA-mediated inhibition of Bcl-XL in TcdA-resistant SKOV3ip1 cells enhanced TcdA-induced cell death. Overexpression of the antiapoptotic proteins Bcl-2 and Bcl-XL in T84 cells also inhibited TcdA-induced cell death. Altogether, our data demonstrate that TcdA induces cell death in both ovarian and colonic cancer cells preferentially via the mitochondrial pathway of apoptosis by a death receptor-independent and a caspase-independent mechanism. This process is regulated by antiapoptotic members of the Bcl-2 family.

* Corresponding author. Mailing address: Département de Microbiologie, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, Québec, Canada J1H 5N4. Phone: (819) 564-5321. Fax: (819) 564-5392. E-mail: alain.piche{at}usherbrooke.ca

{triangledown} Published ahead of print on 21 September 2009.

Editor: V. J. DiRita

Infection and Immunity, December 2009, p. 5400-5410, Vol. 77, No. 12
0019-9567/09/$08.00+0     doi:10.1128/IAI.00485-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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