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Death Pathways Activated in CaCo-2 Cells by Clostridium perfringens Enterotoxin

Ganes Chakrabarti,¹ Xin Zhou,^2, and Bruce A. McClane^1*

Departments of Molecular Genetics and Biochemistry,¹ Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261²

Received 28 February 2003/ Returned for modification 11 April 2003/ Accepted 16 May 2003

Clostridium perfringens enterotoxin (CPE), a 35-kDa polypeptide, induces cytotoxic effects in the enterocyte-like CaCo-2 cell culture model. To identify the mammalian cell death pathway(s) mediating CPE-induced cell death, CaCo-2 cultures were treated with either 1 or 10 µg of CPE per ml. Both CPE doses were found to induce morphological damage and DNA cleavage in CaCo-2 cells. The oncosis inhibitor glycine, but not a broad-spectrum caspase inhibitor, was able to transiently block both of those pathological effects in CaCo-2 cells treated with the higher, but not the lower, CPE dose. Conversely, a caspase 3/7 inhibitor (but not glycine or a caspase 1 inhibitor) blocked morphological damage and DNA cleavage in CaCo-2 cells treated with the lower, but not the higher, CPE dose. Collectively, these results indicate that lower CPE doses cause caspase 3/7-dependent apoptosis, while higher CPE doses induce oncosis. Apoptosis caused by the lower CPE dose was shown to proceed via a classical pathway involving mitochondrial membrane depolarization and cytochrome c release. As the CPE concentrations used in this study for demonstrating apoptosis and oncosis have pathophysiologic relevance, these results suggest that both oncosis and apoptosis may occur in the intestines during CPE-associated gastrointestinal disease.

Editor: J. T. Barbieri

Present address: Center for Vaccine Development and Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201.

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