title: Death pathways activated in CaCo-2 cells by Clostridium perfringens enterotoxin.
abstract: 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 micro g 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.
authors.affiliation: Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Ganes
authors.initials: G
authors.lastname: Chakrabarti
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Bruce A
authors.initials: BA
authors.lastname: McClane
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D003015:Clostridium Infections / Q000473:pathology; D003016:Clostridium perfringens / Q000472:pathogenicity*; D004249:DNA Damage; D020895:Enterocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004768:Enterotoxins / Q000633:toxicity*; D005767:Gastrointestinal Diseases / Q000473:pathology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism
chemical_list: D061945:Caspase Inhibitors; D004768:Enterotoxins; C035598:enterotoxin, Clostridium; D020169:Caspases