Cathepsin D–Bax death pathway in oxidative stressed neuroblastoma cells

Castino, Roberta; Bellio, Natascia; Nicotra, Giuseppina; Follo, Carlo; Trincheri, Nicol F.; Isidoro, Ciro

doi:10.1016/j.freeradbiomed.2006.12.030

Cited by 81 publications

(76 citation statements)

References 39 publications

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“…This phenomenon has been described under in vitro paradigms using a variety of toxic insults (29,44,(73)(74)(75)(76)(77) and in some animal models of neurodegenerative disorders (78 -80). The present study clearly showed that degeneration of neurons following U18666A treatment is accompanied by an increased activity and cytosolic levels of cathepsin D, as observed in toxicity induced by oxidative stress (81). This is supported by three distinct lines of evidence: (i) U18666A-induced toxicity was associated with increased levels of cytochrome c and activation of caspase-9 and caspase-3; (ii) cathepsin D inhibitor pepstatin A significantly protected hippocampal neurons against U18666A-induced toxicity by attenuating the aforesaid signaling mechanisms; and (iii) down-regulation of the cathepsin D level by siRNA treatment was found to protect cultured N2a cells against U18666A-mediated toxicity, whereas overexpression of the enzyme was sufficient to induce cell death.…”

Section: Discussionsupporting

confidence: 68%

Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Amritraj

Wang

Revett

et al. 2013

Journal of Biological Chemistry

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Background: Cathepsin D has been implicated in Niemann-Pick type C (NPC) disease, which is associated with intracellular cholesterol accumulation. Results: Increased cytosolic and extracellular levels of cathepsin D enhanced neuronal death via different mechanisms. Conclusion: Leakage of cathepsin D within and outside the cell can cause cell death. Significance: Cathepsin D may be involved in the degeneration of neurons in NPC pathology.

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Section: Discussionsupporting

confidence: 68%

Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Amritraj

Wang

Revett

et al. 2013

Journal of Biological Chemistry

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“…Another prominent pathway involves mitochondrial damage, cytochrome c release, and caspase-dependent apoptosis (Cheung et al, 2005). Recent evidence suggests that LMP and release of acidic hydrolases into the cytosol may constitute yet another pathway of oxidative cell death (Kroemer and Jaattela, 2005;Blomgran et al, 2007;Castino et al, 2007;Stoka et al, 2007). The first two mechanisms have been extensively investigated in the nervous system, whereas the third has not been analyzed in detail in neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Levels of HNE are elevated in Alzheimer's disease brains and amyotrophic lateral sclerosis spinal cords (Pedersen et al, 1998;Volkel et al, 2006;Williams et al, 2006). Exposure of cultured neurons to HNE triggers cell death via LMP (Castino et al, 2007). Moreover, toxic aldehydes, such as HNE, react with various proteins and cause their dysfunction (Yoritaka et al, 1996;Sayre et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Zinc and 4-Hydroxy-2-Nonenal Mediate Lysosomal Membrane Permeabilization Induced by H₂O₂in Cultured Hippocampal Neurons

Hwang¹,

Lee²,

Kim³

et al. 2008

J. Neurosci.

135

118

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Lysosomal membrane permeabilization (LMP) is implicated in cancer cell death. However, its role and mechanism of action in neuronal death remain to be established. In the present study, we investigate the function of cellular zinc in oxidative stress-induced LMP using hippocampal neurons. Live-cell confocal microscopy with FluoZin-3 fluorescence showed that H 2 O 2 exposure induced vesicles containing labile zinc in hippocampal neurons. Double staining with LysoTracker or MitoTracker disclosed that the majority of the zinccontaining vesicles were lysosomes and not mitochondria.

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“…Release of the proapoptotic lysosomal cathepsins is also known to induce Bax activation and mitochondrial destabilization following exposure to a variety of stimuli (56,57). Therefore, the involvement of cathepsins, as well as calpains, was accessed following LL-37 exposure.…”

Section: Discussionmentioning

confidence: 99%

The Human Host Defense Peptide LL-37 Induces Apoptosis in a Calpain- and Apoptosis-Inducing Factor–Dependent Manner Involving Bax Activity

Mader

Mookherjee

Hancock

et al. 2009

Molecular Cancer Research

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LL-37 is a human cationic host defense peptide (antimicrobial peptide) belonging to the cathelicidin family of peptides. In this study, LL-37 was shown to kill Jurkat T leukemia cells via apoptosis. A loss of mitochondrial membrane potential, DNA fragmentation, and phosphatidylserine externalization were detected following LL-37 exposure, whereas apoptosis was independent of caspase family members. The specific apoptotic pathway induced by LL-37 was defined through the utilization of Jurkat cells modified to express antiapoptotic proteins, as well as cells deficient in various proteins associated with apoptosis. Of interest, both Bcl-2-overexpressing cells and cells deficient in Bax and Bak proteins displayed a significant reduction in LL-37-induced apoptosis. In addition, Jurkat cells modified in the Fas receptor-associated pathway showed no reduction in apoptosis when exposed to LL-37. Analysis of the involvement of apoptosis-inducing factor (AIF) in LL-37-mediated apoptosis revealed that AIF transferred from the mitochondria to the nucleus of cells exposed to LL-37, where it may lead to large-scale DNA fragmentation and chromatin condensation. AIF knockdown analysis resulted in LL-37-resistant cells. This suggests that AIF is mandatory in LL-37-mediated killing. Lastly, chelation or inhibition of Ca 2+ or calpains inhibited LL-37-mediated killing. Further analysis revealed that calpains were required for LL-37-mediated Bax translocation to mitochondria. Together, these data show that LL-37-induced apoptosis is mediated via the mitochondria-associated pathway in a caspase-independent and calpain-and AIF-dependent manner that involves Bax activation and translocation to mitochondria. (Mol Cancer Res 2009;7(5):689-702)

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Cathepsin D–Bax death pathway in oxidative stressed neuroblastoma cells

Cited by 81 publications

References 39 publications

Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Zinc and 4-Hydroxy-2-Nonenal Mediate Lysosomal Membrane Permeabilization Induced by H₂O₂in Cultured Hippocampal Neurons

The Human Host Defense Peptide LL-37 Induces Apoptosis in a Calpain- and Apoptosis-Inducing Factor–Dependent Manner Involving Bax Activity

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Cathepsin D–Bax death pathway in oxidative stressed neuroblastoma cells

Cited by 81 publications

References 39 publications

Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Role of Cathepsin D in U18666A-induced Neuronal Cell Death

Zinc and 4-Hydroxy-2-Nonenal Mediate Lysosomal Membrane Permeabilization Induced by H2O2in Cultured Hippocampal Neurons

The Human Host Defense Peptide LL-37 Induces Apoptosis in a Calpain- and Apoptosis-Inducing Factor–Dependent Manner Involving Bax Activity

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Zinc and 4-Hydroxy-2-Nonenal Mediate Lysosomal Membrane Permeabilization Induced by H₂O₂in Cultured Hippocampal Neurons