Anti-apoptotic oncogenes prevent caspase-dependent and independent commitment for cell death

Abstract

Apoptosis is a morphologically defined type of cell death associated with the activation of certain proteases belonging to the ICE/CED-3 family, known as caspases. Resistance to apoptosis has been implicated as one of the mechanisms that participates in oncogenesis. We found that the broadspectrum peptide inhibitor of the caspases, zVAD-fmk, interferes in a dose-dependent way with all the morphological and biochemical changes associated with apoptosis induced by anti-CD95 mAb, staurosporine, VP-16 and Act-D. However, with the exception of anti-CD95-triggered apoptosis, the insulted cells lost their clonogenic potential, even when pretreated with a high dose of zVAD-fmk. Under these circumstances, the dying cells displayed no signs of apoptosis, including activation of caspases, externalization of phosphatidylserine, nuclear condensation, or DNA fragmentation. Instead, this cell death was characterized by cytoplasmic and nuclear vacuolization followed by the loss of plasma membrane integrity. Thus, preventing the onset of apoptosis by blocking caspase activity did not rescue cells from dying in response to drugs such as staurosporine, VP-16 and Act-D. In comparison, ectopic expression of antiapoptotic oncogenes such as bcl-2 and bcr-abl not only inhibited apoptosis but also preserved the clonogenic potential of the cells. Therefore, oncogenesis is promoted not by simply interfering with caspase-mediated apoptosis, but by preventing an upstream event which we define as the commitment point for cell death.

IL-4 inhibits apoptosis and prevents mitochondrial damage without inducing the switch to necrosis observed with caspase inhibitors

“…Thus, pretreatment of Jurkat cells with zVADfmk inhibited anti-CD95 mAb triggered apoptosis, but not drug-induced apoptosis, with actual cell survival and maintenance of clonogenic potential, suggesting caspasedependent or caspase-independent commitment to cell death, according to circumstances. 40 This could provide an explanation for the opposite results concerning the consequences of caspase inhibition. However, in the present study, zVAD-fmk partly protected thymocytes from spontaneous and from dexamethasone-induced apoptosis while it totally failed to prevent the commitment to cell death in similarly treated B cells.…”

Activation of Stress-activated Protein Kinase/c-Jun NH2-terminal Kinase and p38 Kinase in Calphostin C-induced Apoptosis Requires Caspase-3-like Proteases but Is Dispensable for Cell Death

“…This applies to a number of different models of apoptosis induced by overexpression of bax (55), c-myc overexpression, and serum withdrawal or overexpression of bak (56), protonophore, protoporphyrine IX, dexamethasone, ceramide, etoposide, or nitric oxide (57-62) and cytotoxic T lymphocyte granule exocytosis (63). However, Bcl-2 maintains survival of cells that have been induced to die in a caspase-independent manner with glucocorticoids, growth factor withdrawal, c-Myc, Bax, or Bak (55,56,61,62). Therefore, the down-regulation of Bcl-2 in calphostin C-induced apoptosis is an important commitment event that determines whether or not a cell dies even when it is independent of caspase activation.…”

The p53-inducible apoptotic protein AMID is not required for normal development and tumor suppression

“…In addition to the classic apoptotic pathways, studies have demonstrated that cytochrome c-, Apaf-1-, or caspases-deficient cells can still undergo apoptosis (Kuida et al, 1996;Cecconi et al, 1998;Hakem et al, 1998;Yoshida et al, 1998;Li et al, 2000). In addition, apoptosis induced by some stimuli cannot be inhibited by the pan-caspase inhibitor z-VAD-fmk (Amarante-Mendes et al, 1998;Bidere and Senik, 2001). These studies suggest that caspase-independent apoptotic pathways exist.…”