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.

Cellular patterns of the atrophic response in murine soleus and gastrocnemius muscles submitted to simulated weightlessness

“…However, the magnitude and time course of apoptotic and necrotic mechanisms during 1 week of hindlimb suspension are not the same in different types of muscle, making it difficult to define a common pattern of atrophic mechanisms in skeletal muscles. In fact, the analysis of cell death mechanisms regarding the muscle phenotype suggests that apoptosis prevails in slow muscles, although some inflammatory activity was noticed following the peak of apoptotic activity, which seems in agreement with the aponecrosis theory (Formigli et al 2000;Papucci et al 2004). In the gastrocnemius, some apoptotic and necrotic activity was found earlier in time compared to the soleus muscle.…”

“…So the term ''aponecrosis'', rather than apoptosis or necrosis alone, may explain the cellular and morphological adaptations observed in atrophic conditions in a similar way as previously described by Formigli et al (2000) for fibroblast cell lines. The biochemical and morphological data from the present study when collectively evaluated clearly demonstrate a shift from apoptosis to necrosis, which according to Papucci et al (2004) is a condition for the onset of aponecrosis. However, the magnitude and time course of apoptotic and necrotic mechanisms during 1 week of hindlimb suspension are not the same in different types of muscle, making it difficult to define a common pattern of atrophic mechanisms in skeletal muscles.…”

ERK1/2 Activation Mediates Aβ Oligomer-induced Neurotoxicity via Caspase-3 Activation and Tau Cleavage in Rat Organotypic Hippocampal Slice Cultures

“…Several studies have reported that both apoptosis and necrosis may occur in parallel during neurodegeneration (51). In addition, biphasic cell death, beginning with acute necrosis followed by a delayed apoptosis, the hybrid forms of neuronal death, and/or switch from apoptosis to necrosis strongly support this view (52,53). Further experiments are necessary to clearly establish the connection between apoptosis and necrosis induced by the A␤ oligomer in the hippocampus.…”

Membrane Protected Apoptotic Trophoblast Microparticles Contain Nucleic Acids

“…17 Aponecrosis is a form of cell death that has overlapping morphological features between apoptosis and necrosis in response to hypoxia 39 and chemical-induced hypoxia. 40, 41 Huppertz et al reported that syncytiotrophoblasts exposed to severe hypoxia displayed both apoptotic and necrotic characteristics, suggesting aponecrosis. 17 Consistent with this, our results show that cells treated with rotenone, which blocks the mitochondrial complex I, display fragmented DNA and PI uptake (26%) by 24 hours, whereas by 48 hours, the percentage of PI ϩ cells increased to 73% (Supplemental Figure 2, see http://ajp.amjpathol.org).…”