Multidomain Bcl-2 homolog Bax but not Bak mediates synergistic induction of apoptosis by TRAIL and 5-FU through the mitochondrial apoptosis pathway

Haefen, Clarissa von; Gillissen, Bernhard; Hemmati, Philipp; Wendt, Jana; Güner, Dilek; Mrozek, A.; Belka, Claus; Dörken, Bernd; Daniel, Peter T.

doi:10.1038/sj.onc.1207971

Cited by 79 publications

(94 citation statements)

References 50 publications

(52 reference statements)

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“…The critical role of both Bak and Bax during apoptosis induction by p14 ARF is further underlined by the observation that their combined loss completely impaired mitochondrial activation, as evidenced by the failure of Bax/Bak double-deficient cells to release cytochrome c upon p14 ARF expression. This is in clear contrast to other proapoptotic stimuli, that is, death receptor ligands such as TRAIL (von Haefen et al, 2004;Wendt et al, 2005) or the BH3-only proteins Nbk (Gillissen et al, 2003) or Puma (Yu et al, 2003) that completely rely on the presence of Bax, but not Bak, to facilitate the activation of mitochondria and subsequent execution of apoptotic cell death in human cancer cells. Consequently, we observed that epirubicininduced apoptosis occurred in a predominantly Baxdependent manner in our systems.…”

Section: Discussionmentioning

confidence: 96%

“…Proapoptotic Bak is controlled preferentially by Bcl-x L and Mcl-1 until released by proapoptotic signals, that is, by Noxa (Mcl-1) and Bad (Bcl-x L ) (Willis et al, 2005). These proteins appear to play selective roles, which may delineate a higher degree of specificity to the regulation of Bax and Bak in p14 ARF -induced cell death in analogy to other apoptosis-promoting stimuli (Theodorakis et al, 2002;Gillissen et al, 2003;Yu et al, 2003;von Haefen et al, 2004;Wendt et al, 2005), which clearly demands further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Most studies addressing the impact of Bax and Bak on apoptosis sensitivity of cancer cells therefore suggest that both proteins are partially redundant. Nevertheless, recent evidence delineates that Bax and Bak exert also nonredundant activities Cartron et al, 2003;Gillissen et al, 2003;von Haefen et al, 2004;Wendt et al, 2005). At the molecular level, this may be reflected by the fact that Bax and Bak are differentially controlled by additional factors such as VDAC2 (Cheng et al, 2003;Chandra et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

et al. 2006

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In contrast to the initial notion that the biological activity of p14 ARF strictly depends on a functional mdm-2/p53 signaling axis, we recently demonstrated that p14 ARF mediates apoptosis in a p53/Bax-independent manner. Here, we show that p14 ARF induces breakdown of the mitochondrial membrane potential and cytochrome c release before triggering caspase-9-and caspase-3/7-like activities in p53/Bax-deficient DU145 prostate cancer cells expressing wild-type Bak. Re-expression of Bax in these cells failed to further enhance p14 ARF -induced apoptosis, suggesting that p14 ARF -induced apoptosis primarily depends on Bak but not Bax in these cells. To further define the role of Bak and Bax in p14 ARF -induced mitochondrial apoptosis, we employed short interference RNA for the knockdown of bak in isogeneic, p53 wildtype HCT116 colon cancer cells either proficient or deficient for Bax. There, combined loss of Bax and Bak attenuated p14 ARF -induced apoptosis whereas single loss of Bax or Bak was only marginally effective, as in the case of DU145. Notably, HCT116 cells deficient for Bax and Bak failed to release cytochrome c and showed attenuated activation of caspase-9 (LEHDase) and caspase-3/caspase-7 (DEVDase) upon p14 ARF expression. These data indicate that p14 ARF triggers apoptosis via a Bax/Bakdependent pathway in p53-proficient HCT116, whereas Bax is dispensable in p53-deficient DU145 cells. Nevertheless, a substantial proportion of p14 ARF -induced cell death proceeds in a Bax/Bak-independent manner. This is also the case for inhibition of clonogenic growth that occurs, at least in part, through an entirely Bax/Bakindependent mechanism.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

et al. 2006

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“…Several studies in HCT116 and other cell line models have indicated that Bak cannot compensate for loss of Bax to induce apoptosis in response to TRAIL (LeBlanc et al, 2002;Theodorakis et al, 2002;Han et al, 2004;von Haefen et al, 2004). HCT116 Bax-null cells express similar levels of Bak as the parental cells (Figure 1a), and Bak has been shown to be functional in HCT116 Bax-null cells (Theodorakis et al, 2002).…”

Section: Discussionmentioning

confidence: 97%

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

et al. 2008

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Death receptors can directly (type I cells) or indirectly induce apoptosis by activating mitochondrial-regulated apoptosis (type II cells). The level of caspase 8 activation is thought to determine whether a cell is type I or II, with type II cells less efficient at activating this caspase following death receptor activation. FLICE-inhibitory protein (FLIP) blocks death receptor-mediated apoptosis by inhibiting caspase 8 activation; therefore, we assessed whether silencing FLIP could convert type II cells into type I. FLIP silencing-induced caspase 8 activation in Bax wild-type and null HCT116 colorectal cancer cells; however, complete caspase 3 processing and apoptosis were only observed in Bax wild-type cells. Bax-null cells were also more resistant to chemotherapy and tumor necrosis factor-related apoptosis inducing ligand and, unlike the Bax wild-type cells, were not sensitized to these agents by FLIP silencing. Further analyses indicated that release of second mitochondrial activator of caspases from mitochondria and subsequent inhibition of X-linked inhibitor of apoptosis protein (XIAP) was required to induce full caspase 3 processing and apoptosis following FLIP silencing. These results indicate that silencing FLIP does not necessarily bypass the requirement for mitochondrial involvement in type II cells. Furthermore, targeting FLIP and XIAP may represent a therapeutic strategy for the treatment of colorectal tumors with defects in mitochondrial-regulated apoptosis.

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“…First, we determined the DC m dissipation by means of the DC m -sensitive fluorochrome 3,3 dihexyloxacarbocyanine iodide (DiOC 6 (3)) ( Figures 2a and b). Second, we assessed the relocation of a Bax-GFP fusion protein (von Haefen et al, 2004) from Thapsigargin restores immunogenic cancer cell death I Martins et al a diffuse to a punctate (presumably mitochondrial) pattern (Figures 2c and d). Thus, both CDDP and OXP induced similar mitochondrial perturbations (Figure 2).…”

Section: Thapsigargin Restores Immunogenic Cancer Cell Death I Martinmentioning

confidence: 99%

Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress

et al. 2010

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In contrast to other cytotoxic agents including anthracyclins and oxaliplatin (OXP), cisplatin (CDDP) fails to induce immunogenic tumor cell death that would allow to stimulate an anticancer immune response and hence to amplify its therapeutic efficacy. This failure to induce immunogenic cell death can be attributed to CDDP's incapacity to elicit the translocation of calreticulin (CRT) from the lumen of the endoplasmic reticulum (ER) to the cell surface. Here, we show that, in contrast to OXP, CDDP is unable to activate the protein kinase-like ER kinase (PERK)-dependent phosphorylation of the eukaryotic translation initiation factor 2a (eIF2a). Accordingly, CDDP also failed to stimulate the formation of stress granules and macroautophagy, two processes that only occur after eIF2a phosphorylation. Using a screening method that monitors the voyage of CRT from the ER lumen to the cell surface, we identified thapsigargin (THAPS), an inhibitor of the sarco/ER Ca 2 þ -ATPase as a molecule that on its own does not stimulate CRT exposure, yet endows CDDP with the capacity to do so. The combination of ER stress inducers (such as THAPS or tunicamycin) and CDDP effectively induced the translocation of CRT to the plasma membrane, as well as immunogenic cell death, although ER stress or CDDP alone was insufficient to induce CRT exposure and immunogenic cell death. Altogether, our results underscore the contribution of the ER stress response to the immunogenicity of cell death.

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Multidomain Bcl-2 homolog Bax but not Bak mediates synergistic induction of apoptosis by TRAIL and 5-FU through the mitochondrial apoptosis pathway

Cited by 79 publications

References 50 publications

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

Combined inhibition of FLIP and XIAP induces Bax-independent apoptosis in type II colorectal cancer cells

Restoration of the immunogenicity of cisplatin-induced cancer cell death by endoplasmic reticulum stress

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