Mitochondrial cytochrome c release is caspase-dependent and does not involve mitochondrial permeability transition in didemnin B-induced apoptosis

Grubb, David R.; Ly, Jennifer; Vaillant, François; Johnson, Karina L; Lawen, Alfons

doi:10.1038/sj.onc.1204545

Cited by 35 publications

(26 citation statements)

References 57 publications

(59 reference statements)

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“…Although we cannot rule out the possibility that full-length PKC-d could have some role in mediating the apoptotic pathway upstream of the caspase cascade, our results could suggest a positive feedback loop whereby caspase-mediated activation of PKC-d results in amplification of the caspase cascade and subsequent apoptosis. Further supporting this idea, it has been published that cytochrome-c release from mitochondria upon treatment of HL-60 cells with didemnin B, a structural analogue of Aplidin TM , is caspase-dependent, suggesting the existence of a large positive feedback amplification loop (Grubb et al, 2001).…”

Section: Discussionmentioning

confidence: 62%

Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ

et al. 2002

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AplidinTM , a new antitumoural drug presently in phase II clinical trials, has shown both in vitro and in vivo activity against human cancer cells. Aplidin TM effectively inhibits cell viability by triggering a canonical apoptotic program resulting in alterations in cell morphology, caspase activation, and chromatin fragmentation. Pro-apoptotic concentrations of Aplidin TM induce early oxidative stress, which results in a rapid and persistent activation of both JNK and p38 MAPK and a biphasic activation of ERK. Inhibition of JNK and p38 MAPK blocks the apoptotic program induced by Aplidin TM , demonstrating its central role in the integration of the cellular stress induced by the drug. JNK and p38 MAPK activation results in downstream cytochrome c release and activation of caspases -9 and -3 and PARP cleavage, demonstrating the mediation of the mitochondrial apoptotic pathway in this process. We also demonstrate that protein kinase C delta (PKC-d) mediates the cytotoxic effect of Aplidin TM and that it is concomitantly processed and activated late in the apoptotic process by a caspase mediated mechanism. Remarkably, cells deficient in PKC-d show enhanced survival upon drug treatment as compared to its wild type counterpart. PKC-d thus appears as an important component necessary for full caspase cascade activation and execution of apoptosis, which most probably initiates a positive feedback loop further amplifying the apoptotic process.

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Section: Discussionmentioning

confidence: 62%

Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ

et al. 2002

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“…5B) would rule out a role for cytochrome c release and caspase-9 in our experimental model. However, because a significant release of cytochrome c can also be detected in the absence of changes of ⌬⌿m (Grubb et al, 2001), specific experiments were done to investigate the involvement of both cytochrome c and caspase-9 in the apoptosis induced by adenosine analogs. The subcellular localization of cytochrome c was evaluated by Western blotting analysis in the mitochondrial and cytosolic fractions of control untreated cells and of cells exposed to either 2-CA or 2-CdA for various time periods (7, 10, 15, and 24 h).…”

Section: Figmentioning

confidence: 99%

A Key Role for Caspase-2 and Caspase-3 in the Apoptosis Induced by 2-Chloro-2′-deoxy-adenosine (Cladribine) and 2-Chloro-adenosine in Human Astrocytoma Cells

et al. 2003

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Both the anticancer agent 2-chloro-2Ј-deoxy-adenosine (Cladribine) and its derivative 2-chloro-adenosine induce apoptosis of human astrocytoma cells (J Neurosci Res 60: 388 -400, 2000). In this study, we have analyzed the involvement of caspases in these effects. Both compounds produced a gradual and time-dependent activation of "effector" caspase-3, which preceded the appearance of the nuclear signs of apoptosis, suggesting a temporal correlation between these two events. Moreover, the caspase inhibitor N-benzyloxycarbonyl-

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“…The membrane was then washed three times with TBS and incubated with a dilution of 1/1250 horseradish peroxidase-labeled secondary antibody (Amersham Biosciences, Castle Hill, New South Wales, Australia), for 1 h at 37°C. Following three washes, ECL was used as previously described (31).…”

Section: Sodium Dodecyl Sulfate-polyacrylamide Gel Electrophoresis (Smentioning

confidence: 99%

VDAC1 Is a Transplasma Membrane NADH-Ferricyanide Reductase

Baker

Lane

et al. 2004

Journal of Biological Chemistry

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144

142

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Porin isoform 1 or VDAC (voltage-dependent anionselective channel) 1 is the predominant protein in the outer mitochondrial membrane. We demonstrated previously that a plasma membrane NADH-ferricyanide reductase activity becomes up-regulated upon mitochondrial perturbation, and therefore suggested that it functions as a cellular redox sensor. VDAC1 is known to be expressed in the plasma membrane; however, its function there remained a mystery. Here we show that VDAC1, when expressed in the plasma membrane, functions as a NADH-ferricyanide reductase. VDAC1 preparations purified from both plasma membrane and mitochondria fractions exhibit NADH-ferricyanide reductase activity, which can be immunoprecipitated with poly-and monoclonal antibodies directed against VDAC(1). Transfecting cells with pl-VDAC1-GFP, which carries an N-terminal signal peptide, directs VDAC1 to the plasma membrane, as shown by confocal microscopy and FACS analysis, and significantly increases the plasma membrane NADH-ferricyanide reductase activity of the transfected cells. This novel enzymatic activity of the well known VDAC1 molecule may provide an explanation for its role in the plasma membrane. Our data suggest that a major function of VDAC1 in the plasma membrane is that of a NADH(-ferricyanide) reductase that may be involved in the maintenance of cellular redox homeostasis.

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Mitochondrial cytochrome c release is caspase-dependent and does not involve mitochondrial permeability transition in didemnin B-induced apoptosis

Cited by 35 publications

References 57 publications

Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ

Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ

A Key Role for Caspase-2 and Caspase-3 in the Apoptosis Induced by 2-Chloro-2′-deoxy-adenosine (Cladribine) and 2-Chloro-adenosine in Human Astrocytoma Cells

VDAC1 Is a Transplasma Membrane NADH-Ferricyanide Reductase

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