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- Title
Apoptosis shifts to necrosis via intermediate types of cell death by a mechanism depending on c-myc and bcl-2 expression.
- Authors
Papucci, Laura; Formigli, Lucia; Schiavone, Nicola; Tani, Alessia; Donnini, Martino; Lapucci, Andrea; Perna, Federico; Tempestini, Alessio; Witort, Ewa; Morganti, Maria; Nosi, Daniele; Orlandini, Giovanni E.; Zecchi Orlandini, Sandra; Capaccioli, Sergio
- 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 μM). In cells with basal gene expression, apoptosis shifts to aponecrosis/necrosis at 300 μM 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 μM to 100 μM (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 μM (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.
- Subjects
CELL death; CELLS; APOPTOSIS; HYPOXEMIA; ONCOGENES; CANCER genetics
- Publication
Cell & Tissue Research, 2004, Vol 316, Issue 2, p197
- ISSN
0302-766X
- Publication type
Article
- DOI
10.1007/s00441-004-0872-z