Apoptosis shifts to necrosis via intermediate types of cell death by a mechanism depending on c-myc and bcl-2 expression.
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.
Papucci
Laura
L
Department of Experimental Pathology and Oncology, University of Florence, Via le Morgagni 50, 50132 Florence, Italy.
Formigli
Lucia
L
Schiavone
Nicola
N
Tani
Alessia
A
Donnini
Martino
M
Lapucci
Andrea
A
Perna
Federico
F
Tempestini
Alessio
A
Witort
Ewa
E
Morganti
Maria
M
Nosi
Daniele
D
Orlandini
Giovanni E
GE
Zecchi Orlandini
Sandra
S
Capaccioli
Sergio
S
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
D019253:Proto-Oncogene Proteins c-bcl-2; D000968:Antimycin A