Mechanisms of Caspase-Independent Neuronal Death: Energy Depletion and Free Radical Generation

Lang-Rollin, Isabelle; Rideout, Hardy J.; Noticewala, Manish S.; Stefanis, Leonidas

doi:10.1523/jneurosci.23-35-11015.2003

Cited by 90 publications

(51 citation statements)

References 62 publications

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“…It remains unclear whether Survivin plays a direct or indirect role in the DNA repair process; however, it is apparent that disrupting Survivin disrupts double-strand DNA repair capabilities of radiation-resistant GBM cells, thereby sensitizing these cells to radiation-induced cell death. It has been previously demonstrated that energy depletion plays an important role in caspase-independent neuronal cell death (Lang-Rollin et al, 2003). The present study also suggests that Survivin contributes to a hypermetabolic state in GBMs upon radiation expsosure, contributing to their radioresistant phenotypes.…”

Section: Role Of Survivin In Enhancing Radiation Resistancesupporting

confidence: 74%

Survivin enhances radiation resistance in primary human glioblastoma cells via caspase-independent mechanisms

et al. 2004

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The observed radioresistance of human glioblastoma multiforme (GBM) poses a major challenge, which, if overcome, may lead to significant advances in the management of this patient population. There is accumulating evidence from correlative studies that Survivin expression is associated with increased malignant potential of human gliomas. The purpose of this study was to investigate whether Survivin plays a direct role in mediating radiation resistance in primary human glioma cell lines, and, if so, investigating the underlying mechanisms. Our panel of GBM cell lines included two that were relatively radiation resistant (GM20 and GM21) and two that were more radiation sensitive (GM22 and GM23), which demonstrated differential levels of Survivin expression between the two groups. Through the use of adenoviral vectors containing either dominant-negative (pAd-S(T34A)) or wild-type Suvrivin (pAd-S(WT)), we were able to inactivate or overexpress Survivin, respectively. Our findings suggest that Survivin plays a critical role in mediating radiation resistance in primary GBM cells, in part through suppression of apoptotic cell death via a caspase-independent manner. We have identified novel mechanisms by which Survivin may enhance tumor cell survival upon radiation exposure such as regulation of double-strand DNA break repair and tumor cell metabolism, which were most evident in the radiation-resistant cell lines. These differences in Survivin function both in radiation-resistant vs radiation-sensitive cell lines and in the presence vs absence of radiation exposure warrant further investigation and highlight potentially important mechanisms of radiation resistance in these tumors.

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Section: Role Of Survivin In Enhancing Radiation Resistancesupporting

confidence: 74%

Survivin enhances radiation resistance in primary human glioblastoma cells via caspase-independent mechanisms

et al. 2004

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“…In cell culture and animal models, tau phosphorylation can protect cells from apoptosis (Li et al, 2007). The delayed (nonapoptotic) neuronal death in the rTg4510 model may be similar to that observed in cultured neurons when delayed caspase-independent death is observed in cells treated with an apoptosis-inducing agent while caspases are inhibited (Lang-Rollin et al, 2003).…”

Section: Discussionmentioning

confidence: 77%

In VivoImaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons

Spires‐Jones¹,

Calignon²,

Matsui³

et al. 2008

J. Neurosci.

122

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Accumulation of neurofibrillary tangles (NFTs) in Alzheimer's disease correlates with neuronal loss and cognitive decline, but the precise relationship between NFTs and neuronal death and downstream mechanisms of cell death remain unclear. Caspase cleaved products accumulate in tangles, implying that tangles may contribute to apoptotic neuronal death. To test this hypothesis, we developed methods using multiphoton imaging to detect both neurofibrillary pathology and caspase activation in the living mouse brain. We examined rTg4510 mice, a reversible mouse model of tauopathy that develops tangles and neuronal loss. Only a small percentage of imaged neurons were caspase activity positive, but the vast majority of the cells with active caspases contained NFTs. We next tested the hypothesis that caspase activation led to acute, apoptotic neuronal death. Caspase positive cell bodies did not degenerate over hours of imaging, despite the presence of activated executioner caspases. Suppression of the transgene, which stops ongoing death, did not suppress caspase activity. Finally, histochemical assessments revealed evidence of caspase-cleaved tau, but no TUNEL (terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling) positive or apoptotic nuclei. With the novel technique of observing NFTs and caspase activation in the living brain, we demonstrate that aggregated tau in neurons can be associated with caspase activation, but that caspase activation is not sufficient to cause acute neuronal death in this model.

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“…It is possible that this or a similar mechanism may play a role in the nonapoptotic death of DNA damaged neurons with inhibited p53 (Lang-Rollin et al 2003).…”

Section: Transcriptional Inhibition As a Trigger For P53-mediated Neumentioning

confidence: 99%

Inhibition of nucleolar transcription as a trigger for neuronal apoptosis

Kalita

Makonchuk

Gomes

et al. 2008

Journal of Neurochemistry

107

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In post‐mitotic neurons, the mechanisms of the apoptotic checkpoint that is activated by DNA damage remain unclear. Here we show that in cultured cortical neurons, the DNA damaging agent camptothecin (CPT) reduced transcription of rRNA and disrupted nucleolar staining for B23/nucleophosmin suggesting DNA damage‐induced nucleolar stress. Although CPT activated the pro‐apoptotic protein p53, the CPT‐induced nucleolar stress was unaffected by p53 inhibition. In addition, brain‐derived neurotrophic factor‐mediated protection from CPT‐induced apoptosis prevented neither nucleolar stress nor p53 activation. Therefore, inhibition of rRNA transcription might be upstream of the pro‐apoptotic p53 activity. Indeed, short hairpin RNA‐mediated inhibition of a RNA‐Polymerase‐I co‐factor, transcription initiation factor IA, attenuated rRNA transcription causing nucleolar stress and p53‐dependent neuronal apoptosis. The protein synthesis inhibitor cycloheximide blocked apoptosis that was induced by over‐expressed shTIF‐IA or active form of p53. Also, the general transcription inhibitor actinomycin D triggered nucleolar stress and activated p53. However, it did not induce apoptosis except at the low concentration of 0.05 μg/mL with stronger inhibitory activity against nucleolar than extranucleolar transcription. Hence, nucleolar stress‐activated apoptosis requires extranucleolar transcription. This study identifies the nucleoli of post‐mitotic neurons as sensors of DNA damage coupling reduced rRNA transcription to p53‐mediated apoptosis that requires de novo expression of protein‐coding genes. Thus, rDNA selectivity of DNA damage may determine its ability to induce neuronal apoptosis.

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Mechanisms of Caspase-Independent Neuronal Death: Energy Depletion and Free Radical Generation

Cited by 90 publications

References 62 publications

Survivin enhances radiation resistance in primary human glioblastoma cells via caspase-independent mechanisms

Survivin enhances radiation resistance in primary human glioblastoma cells via caspase-independent mechanisms

In VivoImaging Reveals Dissociation between Caspase Activation and Acute Neuronal Death in Tangle-Bearing Neurons

Inhibition of nucleolar transcription as a trigger for neuronal apoptosis

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