Calcium ionophores can induce either apoptosis or necrosis in cultured cortical neurons

Gwag, Byoung Joo; Canzoniero, Lorella M.T.; Sensi, Stefano L.; Demaro, Joseph A.; Koh, Jun Seok; Goldberg, Mark P.; Jacquin, Mark F.; Choi, Doo-Sup

doi:10.1016/s0306-4522(98)00508-9

Cited by 112 publications

(83 citation statements)

References 74 publications

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“…Whereas we have previously shown that loss of calcium is highly correlated with increased apoptosis (Turner et al, 2002;Turner et al, 2004;Turner et al, 2006) in close agreement with many other studies (Koh and Cotman, 1992;Takadera and Ohyashiki, 1998;Gwag et al, 1999;Hwang et al, 1999;Moran et al, 1999;Takadera et al, 1999;Han et al, 2001;Moulder et al, 2002), it was not presently clear if both events can be observed in the same cell. However, we now show that, in the same neuron, decreased CG-1 intensity is correlated with increased AC3-ir, providing new and important evidence that loss of calcium is directly linked to increased apoptosis.…”

Section: -Discussionsupporting

confidence: 82%

“…Before EDAC exposure CG-1 intensity was 195 ± 32 (grayscale units; see Methods) whereas after the crosslinking and ICC procedures was 158 ± 24 (N = 35 cells), indicating a substantial fraction of the original signal was maintained after EDAC/ICC. Because many studies suggest an association between loss of calcium and neuronal injury (Koh and Cotman, 1992;Takadera and Ohyashiki, 1998;Gwag et al, 1999;Hwang et al, 1999;Moran et al, 1999;Han et al, 2001;Moulder et al, 2002;Turner et al, 2002;Yoon et al, 2003;Turner et al, 2004;Turner et al, 2006), we next examined if changes in both CG-1 labeling and increased AC3-immunoreactivity (ir) could be observed in the same cell following loss of intracellular calcium. Thus, primary cortical neurons were exposed to vehicle or 1-20 μM BAPTA for 4 hr, based on previous studies showing this time point is associated with robust apoptosis following loss of calcium (Turner et al, 2002;Turner et al, 2004;Turner et al, 2006).…”

Section: -Resultsmentioning

confidence: 99%

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Loss of calcium and increased apoptosis within the same neuron

et al. 2007

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Loss of neuronal calcium is associated with later apoptotic injury but observing reduced calcium and increased apoptosis in the same cell would provide more definitive proof of this apparent correlation. Thus, following exposure to vehicle or the calcium chelator BAPTA (1-20 μM), primary cortical neurons were labeled with Calcium Green-1 which was then cross-linked with EDAC, prior to immunostaining for various proteins. We found that BAPTA-induced changes in calcium were highly correlated with changes in expression of activated caspase-3 as well as the calcium binding proteins calbindin, calretinin, and parvalbumin. Additionally, in brain slices from P7 neonatal rats, BAPTA induced significant loss of calcium in a brain region we have previously shown to express only moderate levels of calcium binding proteins as well as display robust apoptosis following calcium entry blockade. In contrast, BAPTA had little influence on calcium levels in a brain region we have previously shown to express robust calcium binding proteins as well as display far less apoptosis following calcium entry blockade. These data suggest that the ability of developing neurons to buffer changes in calcium may be critical to their long-term survival.

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Section: -Discussionsupporting

confidence: 82%

Section: -Resultsmentioning

confidence: 99%

Loss of calcium and increased apoptosis within the same neuron

et al. 2007

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“…PMCA2 silencing-mediated effects on breast cancer cell death have focused on ionomycin [5], which can trigger cell death through sustained [Ca 2+ ]CYT increases of high magnitude [5,7,8].…”

Section: Introductionmentioning

confidence: 99%

PMCA2 silencing potentiates MDA-MB-231 breast cancer cell death initiated with the Bcl-2 inhibitor ABT-263

Curry

Roberts‐Thomson

Monteith

2016

Biochemical and Biophysical Research Communications

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PMCA2 overexpression in some breast cancers suggests that this calcium pump isoform may play a role in breast pathophysiology. To investigate PMCA2 as a potential drug target for breast cancer therapy, we assessed the functional consequence of PMCA2 silencing on cell death pathways and calcium signals in the basal-like MDA-MB-231 breast cancer cell line. Silencing PMCA2 expression alone has no effect on MDA-MB-231 cell viability, however, PMCA2 silencing promotes calcium-induced cell death initiated with the calcium ionophore ionomycin.Assessment of cytoplasmic calcium responses generated with various agents including ionomycin demonstrates that in MDA-MB-231 cells, PMCA2 does not play a major role in shaping global calcium signals. We also examined the ability of PMCA2 silencing to modulate caspase-dependent cell death triggered by a Bcl-2 inhibitor that is in clinical development for the treatment of various cancers, ABT-263 (Navitoclax). Despite the lack of effect on global calcium responses, PMCA2 silencing augmented Bcl-2 inhibitor (ABT-263)-mediated MDA-MB-231 breast cancer cell death. These studies provide evidence that PMCA2 inhibitors could sensitize PMCA2-positive breast cancers to cell death initiators that work through mechanisms involving the Bcl-2 survival pathway.

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“…17 In a previous study, PTD-FNK was demonstrated to reduce ischemic injury to hippocampal CA1 neurons after a transient forebrain ischemia, 18 which involves slow progressive neuronal degeneration, and an apoptotic pathway is suggested to contribute to the ischemic degeneration, to some extent. 19 The enhanced cytoprotective activity of FNK against oxidative stress and a calcium ionophore give rise to the possibility that FNK effectively protects cells from necrosis as well as apoptosis, because oxidative stress [20][21][22] and a disruption of calcium homeostasis [23][24][25] are known to induce necrosis. Carbon tetrachloride (CCl 4 ) has been used to induce necrosis in control experiments for studies on apoptosis [26][27][28][29] and is one of most typical model agents for studying the pathogenesis of liver injury.…”

Section: Introductionmentioning

confidence: 99%

Zonal necrosis prevented by transduction of the artificial anti-death FNK protein

et al. 2005

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Protection of cells from necrosis would be important for many medical applications. Here, we show protein transduction domain (PTD)-FNK therapeutics based on protein transduction to prevent necrosis and acute hepatic injury with zonal death induced by carbon tetrachloride (CCl 4 ). PTD-FNK is a fusion protein comprising the HIV/Tat PTD and FNK, a gain-offunction mutant of anti-apoptotic Bcl-x L . PTD-FNK protected hepatoma HepG2 from necrotic death induced by CCl 4 , and additionally, increased the apoptotic population among cells treated with CCl 4 . A concomitant treatment with a pancaspase inhibitor Z-VAD-FMK (N-benzyloxycarbonyl-Val-AlaAsp-fluoromethylketone), which alone could not prevent the necrosis, protected these cells from the apoptosis. When preinjected intraperitoneally, PTD-FNK markedly reduced zonal liver necrosis caused by CCl 4 . Moreover, injection of PTD-FNK accompanied by Z-VAD-FMK suppressed necrotic injury even after CCl 4 administration. These results suggest that PTD-FNK has great potential for clinical applications to prevent cell death, whether from apoptosis or necrosis, and organ failure.

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Calcium ionophores can induce either apoptosis or necrosis in cultured cortical neurons

Cited by 112 publications

References 74 publications

Loss of calcium and increased apoptosis within the same neuron

Loss of calcium and increased apoptosis within the same neuron

PMCA2 silencing potentiates MDA-MB-231 breast cancer cell death initiated with the Bcl-2 inhibitor ABT-263

Zonal necrosis prevented by transduction of the artificial anti-death FNK protein

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