Association of Active Caspase 8 with the Mitochondrial Membrane during Apoptosis: Potential Roles in Cleaving BAP31 and Caspase 3 and Mediating Mitochondrion-Endoplasmic Reticulum Cross Talk in Etoposide-Induced Cell Death

Chandra, Dhyan; Choy, Grace; Deng, Xiaolong; Bhatia, Bobby; Daniel, Peter T.; Tang, Dean G.

doi:10.1128/mcb.24.15.6592-6607.2004

Cited by 142 publications

(134 citation statements)

References 63 publications

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“…In fact, we recently observed that caspase-8 may associate with the mitochondrial membrane during drug-induced apoptosis. There, caspase-8 mediates cleavage of caspase-3 and BAP31 which in turn appears to be critical in initiating mitochondria/ER crosstalk (Chandra et al, 2004). In this vein, Bak was shown previously to mediate ER stress-induced cell death (Nutt et al, 2002) and DU145 cells that have lost Bax still express Bak.…”

Section: Discussionmentioning

confidence: 98%

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

et al. 2004

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The death ligand TRAIL synergizes with DNA-damaging therapies such as chemotherapeutic drugs or ionizing irradiation. Here, we show that the synergism of TRAIL and 5-fluorouracil (5-FU) and cross-sensitization between TRAIL and 5-FU for induction of apoptosis, entirely depend on Bax proficiency in human DU145 and HCT116 carcinoma cells. DU145 prostate carcinoma cells that have lost Bax protein expression due to mutation fail to release cytochrome c and to activate caspase-3 and -9 when exposed to TRAIL and 5-FU. In contrast, TRAIL sensitized for 5-FU-induced apoptosis and vice versa upon reconstitution of Bax expression. Isobolographic analyses of ED50 doses for 5-FU at increasing TRAIL concentrations showed a clear synergism of TRAIL and 5-FU in Bax-expressing cells. In contrast, the effect was merely additive in DU145 cells lacking Bax. Notably, both DU145 and HCT116 Bax-deficient cells still express Bak. This indicates that Bak is not sufficient to mediate crosssensitization and synergism between 5-FU and TRAIL. Stable overexpression of Bak in DU145 sensitized for epirubicin-induced apoptosis but failed to confer synergy between TRAIL and 5-FU. Moreover, we show by the use of EGFP-tagged Bax and Bak that TRAIL and 5-FU synergistically trigger oligomerization and clustering of Bax but not Bak. These data clearly establish distinct roles for Bax and Bak in linking the TRAIL death receptor pathway to the mitochondrial apoptosis signaling cascade and delineate a higher degree of specificity in signaling for cell death by multidomain Bcl-2 homologs.

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Section: Discussionmentioning

confidence: 98%

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

et al. 2004

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“…A number of independent studies have observed the association of caspase-8 with the mitochondria, but the purpose of its localized production on the mitochondrial outer membrane has remained unknown. 19,[28][29][30][31][32] Our results suggest that the formation of a death-inducing activation platform on the outer mitochondrial may be needed to effectively target sufficient amounts of BID for the induction of MOMP and to bypass the problem of weak caspase-8 activation at the DISC.…”

Section: Discussionmentioning

confidence: 99%

BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane

et al. 2010

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Caspase-8 stably inserts into the mitochondrial outer membrane during extrinsic apoptosis. Inhibition of caspase-8 enrichment on the mitochondria impairs caspase-8 activation and prevents apoptosis. However, the function of active caspase-8 on the mitochondrial membrane remains unknown. In this study, we have identified a native complex containing caspase-8 and BID on the mitochondrial membrane, and showed that death receptor activation by Fas or tumor necrosis factor-related apoptosisinducing ligand (TRAIL) induced the cleavage of BID (tBID formation) within this complex. tBID then shifted to separate mitochondria-associated complexes that contained other BCL-2 family members, such as BAK and BCL-X L . We report that cells stabilize active caspase-8 on the mitochondria in order to specifically target mitochondria-associated BID, and that BID cleavage on the mitochondria is essential for caspase-8-induced cytochrome c release. Our findings indicate that during extrinsic apoptosis, caspase-8 can specifically target BID where it is mostly needed, on the surface of mitochondria.

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“…To test whether apoptotic stimuli might also induce prosurvival molecules, we employed three apoptotic inducers: serum deprivation to inactivate PI3K/ Akt survival signaling, a DNA-damaging agent etoposide (VP16), and a mitochondrial toxin (BMD188) whose proapoptotic effect requires the mitochondrial respiratory chain (MRC) (Tang et al, 1998;Joshi et al, 1999;Chandra et al, 2002Chandra et al, , 2004. We first determined their effects on proapoptotic Bcl-2 family proteins, in particular, the BH3-only protein Bim and multi-BH-domain proteins Bax and Bak.…”

Section: Resultsmentioning

confidence: 99%

“…Apoptosis was qualitatively (caspase-3 activation, PARP cleavage assays, DEVDase and LEHDase activity measurement, and DNA fragmentation) and quantitatively (fluorescence microscopy upon DAPI or annexin V-FITC staining) analysed as previously detailed (Tang et al, 1998;Chandra et al, 2002Chandra et al, , 2004Liu et al, 2002).…”

Section: Measurement Of Apoptosismentioning

confidence: 99%

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Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS

et al. 2005

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Most cancer therapeutics fails to eradicate cancer because cancer cells rapidly develop resistance to its proapoptotic effects. The underlying mechanisms remain incompletely understood. Here we show that three representative apoptotic stimuli, that is, serum starvation, a mitochondrial toxin, and a DNA-damaging agent (etoposide), rapidly induce several distinct classes of prosurvival molecules, in particular, Bcl-2/Bcl-X L and superoxide dismutase (SOD; including both MnSOD and Cu/ ZnSOD). At the population level, the induction of these prosurvival molecules occurs prior to or concomitant with the induction of proapoptotic molecules such as Bim and Bak. Blocking the induction using siRNAs of the prosurvival or proapoptotic molecules facilitates or inhibits apoptosis, respectively. One master transcription factor, FOXO3a, is involved in the transcriptional activation of some of these prosurvival (e.g., MnSOD) and proapoptotic (e.g., Bim) molecules. Interestingly, in all three apoptotic systems, FOXO3a itself is also upregulated at the transcriptional level. Mechanistic studies indicate that reactive oxygen species (ROS) are rapidly induced upon apoptotic stimulation and that ROS inhibitors/scavengers block the induction of FOXO3a, MnSOD, and Bim. Finally, we show that apoptotic stimuli also upregulate prosurvival molecules in normal diploid human fibroblasts and at subapoptotic concentrations. Taken together, these results suggest that various apoptotic inducers may rapidly mobilize prosurvival mechanisms through ROS-activated master transcription factors such as FOXO3a. The results imply that effective anticancer therapeutics may need to combine both apoptosis-inducing and survival-suppressing strategies.

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Association of Active Caspase 8 with the Mitochondrial Membrane during Apoptosis: Potential Roles in Cleaving BAP31 and Caspase 3 and Mediating Mitochondrion-Endoplasmic Reticulum Cross Talk in Etoposide-Induced Cell Death

Cited by 142 publications

References 63 publications

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

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

BID is cleaved by caspase-8 within a native complex on the mitochondrial membrane

Induction of prosurvival molecules by apoptotic stimuli: involvement of FOXO3a and ROS

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