title: Apoptosis shifts to necrosis via intermediate types of cell death by a mechanism depending on c-myc and bcl-2 expression.
abstract: Hypoxic and chemical hypoxia (antimycin A) commits cultured rat fibroblasts (Rat-1) towards apoptosis, necrosis or an intermediate form of cell death (aponecrosis) depending on the degree of hypoxia. Aponecrosis also occurs in vivo. Here, we demonstrate that c-myc and bcl-2, two proto-oncogenes known to lower or to enhance, respectively, the apoptotic threshold, also affect the type of cell death: apoptosis shifts to aponecrosis and aponecrosis to necrosis, depending on c-myc or bcl-2 expression and the antimycin A concentration (100-400 microM). In cells with basal gene expression, apoptosis shifts to aponecrosis/necrosis at 300 microM antimycin A (middle hypoxia). Overexpression of c-myc markedly increases cumulative cell death in response to antimycin A and lowers the antimycin A concentration required to shift apoptosis to aponecrosis/necrosis from 300 microM to 100 microM (low hypoxia). Overexpression of bcl-2 elicits the opposite effect, decreasing cumulative cell death in response to antimycin A and raising the drug concentration required to shift apoptosis to aponecrosis/necrosis to 400 microM (high hypoxia). The passage from one to the other form of cell death involves various aponecrotic features with observed intermediate aspects between apoptosis and necrosis, a progressive increase in necrotic features being correlated with an increase in antimycin A concentration. The mechanism underlying the various effects of c-myc and bcl-2 on cell-death type has been related to the ability of these genes to counteract, to various extents, the ATP decrease occurring in response to different degrees of chemical hypoxia.
authors.affiliation: Department of Experimental Pathology and Oncology, University of Florence, Via le Morgagni 50, 50132 Florence, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Papucci
authors.forename: Lucia
authors.initials: L
authors.lastname: Formigli
authors.forename: Nicola
authors.initials: N
authors.lastname: Schiavone
authors.forename: Alessia
authors.initials: A
authors.lastname: Tani
authors.forename: Martino
authors.initials: M
authors.lastname: Donnini
authors.forename: Andrea
authors.initials: A
authors.lastname: Lapucci
authors.forename: Federico
authors.initials: F
authors.lastname: Perna
authors.forename: Alessio
authors.initials: A
authors.lastname: Tempestini
authors.forename: Ewa
authors.initials: E
authors.lastname: Witort
authors.forename: Maria
authors.initials: M
authors.lastname: Morganti
authors.forename: Daniele
authors.initials: D
authors.lastname: Nosi
authors.forename: Giovanni E
authors.initials: GE
authors.lastname: Orlandini
authors.forename: Sandra
authors.initials: S
authors.lastname: Zecchi Orlandini
authors.forename: Sergio
authors.initials: S
authors.lastname: Capaccioli
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D016259:Genes, myc / Q000235:genetics / Q000502:physiology*; D046529:Microscopy, Electron, Transmission; D009336:Necrosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D000968:Antimycin A