Bcl-2 down-regulation causes autophagy in a caspase-independent manner in human leukemic HL60 cells

Abstract

To understand the roles of bcl-2 for the survival of leukemic cells, we constructed human leukemic HL60 transformant lines in which full length bcl-2 antisense message was conditionally expressed by a tetracycline-regulatable expression system. Cell growth was completely inhibited after antisense message induction and massive cell death was induced. Electron microscopic examinations show that cells died by autophagy, but not by apoptosis. The morphology and the function of mitochondria remained intact: neither the reduction in mitochondrial membrane potential nor the nuclear translocation of AIF, a mitochondrial protein that translocates to nuclei in cases of apoptosis, was observed. Caspase inhibitors did not rescue bcl-2-antisense-mediated autophagy. Thus, bcl-2 is essential for leukemic cell survival and its down-regulation results in autophagy

Autophagy-active beclin-1 correlates with favourable clinical outcome in non-Hodgkin lymphomas

“…Moreover, the presence of LC3-positive vacuoles in relation to the expression and localization of beclin-1 and bcl-2 was compa-tible with the predicted model of bcl-2-mediated regulation of beclin-1-dependent autophagy. 37 Our data are in agreement with the observation of Saeki et al, 38 who reported an increase of basal autophagy in leukaemic cells after downregulation of bcl-2 expression. In a few cases, tumours with a low percentage of beclin-1-positive cells presented with a relative high proportion of LC-3-positive cells, which is suggestive of the activation of a beclin-1-independent autophagy pathway.…”

Autophagy and signaling: their role in cell survival and cell death

“…86 The accumulation of autophagy gene products during cell death, and their relationship with members of the Bcl-2 family, is a promising track to explore in order to obtain a better understanding of how autophagy is controlled during cell death. 68,87 The interaction between Beclin 1 and Bcl-2/Bcl-xL 88 is probably a key event in turning the accumulation of autophagosomes on or off. 68 Mitochondria play a central role in the execution of apoptosis by releasing apoptotic factors.…”

Redundant cell death mechanisms as relics and backups

“…DNA damage or inhibition of protein kinases with staurosporine) induce necrosis when ATP supply is limited. 11 Downmodulation of the antiapoptotic protein Bcl-2 25 or upregulation of the proapoptotic Bcl-2 homolog BNIP3 26 can induce death accompanied by autophagic vacuolization. In mouse embryonic fibroblasts lacking the proapoptotic proteins Bax and Bak, alkylating DNA damage induces a necrotic type of cell death that relies on ATP depletion, 27 and etoposide induces an autophagic type of cell death dependent on autophagy proteins ATG5 and beclin, 28 while both types of damage induce apoptosis in Bax-or Bak-sufficient control cells.…”