Requirement for Aspartate-cleaved Bid in Apoptosis Signaling by DNA-damaging Anti-cancer Regimens

Werner, Arlette B.; Tait, Stephen W.G.; Vries, Evert de; Eldering, Eric; Borst, Jannie

doi:10.1074/jbc.m400268200

Cited by 38 publications

(44 citation statements)

References 62 publications

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“…As mentioned previously, a separate study using Jurkat T cells suggested that tBid was required for apoptosis signaling during DNA damage-induced apoptosis (38). The authors also concluded that Bid cleavage occurred independently of caspase activity.…”

Section: Resultsmentioning

confidence: 75%

“…Furthermore, a different study reported that tBid is important during DNA damage-induced apoptosis and that the cleavage of Bid to tBid in this context was not caspase-dependent. Instead, cleavage was suggested to occur by an unidentified aspartate protease (38). The same study concluded that the importance of tBid for genotoxic stress-induced apoptosis was that it functioned to promote MOMP upstream of caspase activation.…”

Section: Resultsmentioning

confidence: 92%

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Cleavage of Bid by Executioner Caspases Mediates Feed Forward Amplification of Mitochondrial Outer Membrane Permeabilization during Genotoxic Stress-induced Apoptosis in Jurkat Cells

Shelton

Shawgo

Robertson

2009

Journal of Biological Chemistry

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The extent to which the BH3-only protein Bid is important for intrinsic (mitochondria-mediated) apoptotic cell death induced by genotoxic stress remains controversial. In the present study, we examine this issue using a panel of gene-manipulated Baxdeficient Jurkat T-lymphocytes. Cells stably depleted of Bid were far less sensitive than control-transfected cells to etoposide-induced apoptosis. In particular, drug-induced Bak activation, cytochrome c release, loss of mitochondrial membrane potential, and caspase activation were all decreased in cells lacking Bid. Reconstitution experiments using recombinant proteins and permeabilized Bid-deficient cells demonstrated that truncated Bid (tBid), but not full-length Bid, potently induced Bak activation and the release of cytochrome c. Further, caspase-8-deficient Jurkat cells efficiently cleaved Bid and were sensitive to drug-induced apoptosis. By comparison, Apaf-1-deficient cells, as well as cells overexpressing full-length X-linked inhibitor of apoptosis protein (XIAP) or the BIR1/ BIR2 domains of XIAP, failed to cleave Bid in response to genotoxic stress. These data suggest that tBid plays an important regulatory role in the execution of DNA damage-induced cytochrome c release and apoptosis. However, the fact that cleavage of Bid to tBid is mediated by executioner caspases suggests that a self-amplifying feed forward loop involving caspases, Bid, and mitochondria may help determine irreversible commitment to apoptosis.Apoptosis is an active form of cell death that plays an essential role during normal embryonic development and in the maintenance of tissue homeostasis in the adult organism (1). Consequently, dysregulation of apoptosis has been implicated as a contributing factor to the onset of different pathological conditions, including cancer. In addition, it is now generally accepted that many genotoxic anticancer drugs are effective against tumor cells for their ability to induce mitochondriamediated apoptosis (2). Similarly, mutations or the altered expression of pro-and anti-apoptotic proteins can contribute to the development of drug resistance.Execution of apoptosis is mediated by a family of cysteinedependent aspartate-specific proteases (caspases). During true mitochondria-mediated apoptosis, members of the Bcl-2 family of proteins are the primary regulators of caspase activation for their role in controlling mitochondrial outer membrane permeabilization (MOMP) 2 (3). The process of MOMP results in the release of cytochrome c, second mitochondria-derived activator of caspase (Smac, also known as DIABLO), and Omi (also known as HtrA2) into the cytosol where they converge to promote the activation of caspase-9 within the apoptotic protease-activating factor-1 (Apaf-1) apoptosome complex. The Bcl-2 family contains proteins with opposing functions, and it is generally thought that the induction of MOMP requires the activation of either Bak or Bax triggered by a Bcl-2 homology 3 (BH3)-only protein (4 -6). Indeed, evidence in the literature indicates that cel...

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Section: Resultsmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 92%

Cleavage of Bid by Executioner Caspases Mediates Feed Forward Amplification of Mitochondrial Outer Membrane Permeabilization during Genotoxic Stress-induced Apoptosis in Jurkat Cells

Shelton

Shawgo

Robertson

2009

Journal of Biological Chemistry

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Section: Cells and Stimulationmentioning

confidence: 99%

“…These cells have one wild-type and one mutant p53 allele and undergo DNA damage-induced apoptosis in a p53-independent manner (Werner et al, 2004;Wissink et al, 2006). J16 cells, stably overexpressing Bcl-2 (J16-Bcl-2) or the dnCaspase-9 active site mutant C287A (J16-dnC9), were generated by retroviral transduction (Werner et al, 2004). For apoptosis assays, J16 cells were stimulated with the indicated doses of death receptor ligand, etoposide or IR in Iscove's modified Dulbecco's medium with 5% fetal bovine serum and cultured for the indicated time periods at 371C, 5% CO 2 .…”

Section: Cells and Stimulationmentioning

confidence: 99%

Ionizing radiation modulates the TRAIL death-inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway

et al. 2007

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In many tumor cell types, ionizing radiation (IR) or DNA-damaging anticancer drugs enhance sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, which is of great clinical interest. We have investigated the molecular mechanism underlying the response to combined modality treatment in p53-mutant Jurkat T leukemic cells overexpressing Bcl-2. These cells are largely resistant to individual treatment with TRAIL or IR, but sensitive to combined treatment, in vitro as well as in vivo. We demonstrate that IR and DNA-damaging anticancer drugs enable TRAIL receptor-2 and CD95/Fas to bypass the mitochondrial pathway for effector caspase activation. This was validated by RNA interference for Bax and Bak and by overexpression of dominant-negative Caspase-9. Improved effector caspase activation was neither caused by altered expression of proapoptotic components nor by impaired activity of inhibitor of apoptosis proteins or nuclear factor-jB signaling. Rather, we found that pretreatment of cells with IR caused quantitative and qualitative changes in death receptor signaling. It strongly improved the capacity of ligand-bound receptors to recruit FADD and activate Caspase-8 and -10 in the death-inducing signaling complex, while c-FLIP L levels were unaffected.

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“…40,48 Caspase 2 appeared to act either upstream or downstream of other caspases depending on the cell type and specific mode investigated. 40,[49][50][51][52][53] Interestingly, caspase 2-mediated cell death was even reported to occur in the absence of any detectable release of mitochondrial factors or even caspase 3 activation, which places caspase 2 independent of both the mitochondrial and death receptor pathways. 38 In cholangiocarcinoma cells, TMX was shown to activate caspase 2, whereas GMT had no effect (Figure 4a).…”

Section: Discussionmentioning

confidence: 99%

Tamoxifen enhances therapeutic effects of gemcitabine on cholangiocarcinoma tumorigenesis

Yuan

Turk

et al. 2011

Laboratory Investigation

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Cholangiocarcinoma is a highly malignant tumor with limited therapeutic options. We have previously reported that tamoxifen (TMX) induces apoptosis of cholangiocarcinoma cells and reduces cholangiocarcinoma tumorigenesis in mice.In the present studies, we determined the effect of combination therapy of TMX and gemcitabine (GMT), another chemotherapeutical reagent for many cancers, on cholangiocarcinoma tumorigenesis and investigated the responsible mechanisms. GMT inhibited cell growth and induced apoptosis of cholangiocarcinoma cells in a concentrationdependent manner. TMX enhanced GMT-induced apoptosis of cholangiocarcinoma cells. Consistently, GMT (15 mg/kg) inhibited cholangiocarcinoma tumorigenesis in nude mice by 50%. TMX (15 mg/kg) enhanced the inhibitory effect of GMT on tumorigenesis by 33%. The inhibition of tumor growth correlated with enhanced apoptosis in tumor tissues. To elucidate the mechanisms underlying the additive effects of TMX on GMT-induced apoptosis, we determined the activation of caspases in cholangiocarcinoma cells exposed to GMT, TMX, or both. Activation of caspases 9 and 3, as well as cytochrome c release to the cytosol, was demonstrated in cells exposed to both reagents. In contrast, TMX activated caspase 2, whereas GMT had no effect. Inhibition of caspase 2 activation decreased TMX-, but not GMT-, induced activation of caspase 3 and apoptosis of cholangiocarcinoma cells. Similarly, activation of caspase 2 was found in tumors from TMX-treated mice, but not GMT-treated mice. Therefore, the enhanced effect of TMX on GMT-induced cholangiocarcinoma cell death is partially mediated by activation of caspase 2. TMX and GMT both induce apoptosis and inhibit cholangiocarcinoma tumorigenesis, which may be attributed to the activation of distinct apoptosis signals by TMX and GMT. Our studies provide in vivo evidence and molecular insight to support the use of TMX and GMT in combination as an effective therapy for cholangiocarcinoma.

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Requirement for Aspartate-cleaved Bid in Apoptosis Signaling by DNA-damaging Anti-cancer Regimens

Cited by 38 publications

References 62 publications

Cleavage of Bid by Executioner Caspases Mediates Feed Forward Amplification of Mitochondrial Outer Membrane Permeabilization during Genotoxic Stress-induced Apoptosis in Jurkat Cells

Cleavage of Bid by Executioner Caspases Mediates Feed Forward Amplification of Mitochondrial Outer Membrane Permeabilization during Genotoxic Stress-induced Apoptosis in Jurkat Cells

Ionizing radiation modulates the TRAIL death-inducing signaling complex, allowing bypass of the mitochondrial apoptosis pathway

Tamoxifen enhances therapeutic effects of gemcitabine on cholangiocarcinoma tumorigenesis

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