Lysosomal destabilization and cathepsin B contributes for cytochrome <i>c</i> release and caspase activation in embelin‐induced apoptosis

Joy, Beena; Sivadasan, Rajeeve; Emilia, Abraham T.; Morser, John; Sobhan, Praveen K.; Seervi, Mahendra; Santhoshkumar, T.R.

doi:10.1002/mc.20599

Cited by 49 publications

(38 citation statements)

References 32 publications

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“…LMP, as a distinct event in the apoptotic pathway, is now widely accepted (16,55,56) and is believed by many to occur upstream of mitochondrial outer membrane permeabilization and caspase-3 activation (57,58). This is consistent with our findings, given that LMP was evoked after 6 h of exposure to A␤, whereas DNA fragmentation and caspase-3 activation typically do not occur at a significant level until 48 h post-A␤ treatment.…”

Section: Discussionsupporting

confidence: 91%

Endocannabinoids Prevent β-Amyloid-mediated Lysosomal Destabilization in Cultured Neurons

Noonan

Tanveer

Klompas

et al. 2010

Journal of Biological Chemistry

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Neuronal cell loss underlies the pathological decline in cognition and memory associated with Alzheimer disease (AD).Recently, targeting the endocannabinoid system in AD has emerged as a promising new approach to treatment. Studies have identified neuroprotective roles for endocannabinoids against key pathological events in the AD brain, including cell death by apoptosis. Elucidation of the apoptotic pathway evoked by ␤-amyloid (A␤) is thus important for the development of therapeutic strategies that can thwart A␤ toxicity and preserve cell viability. We have previously reported that lysosomal membrane permeabilization plays a distinct role in the apoptotic pathway initiated by A␤. In the present study, we provide evidence that the endocannabinoid system can stabilize lysosomes against A␤-induced permeabilization and in turn sustain cell survival. We report that endocannabinoids stabilize lysosomes by preventing the A␤-induced up-regulation of the tumor suppressor protein, p53, and its interaction with the lysosomal membrane. We also provide evidence that intracellular cannabinoid type 1 receptors play a role in stabilizing lysosomes against A␤ toxicity and thus highlight the functionality of these receptors. Given the deleterious effect of lysosomal membrane permeabilization on cell viability, stabilization of lysosomes with endocannabinoids may represent a novel mechanism by which these lipid modulators confer neuroprotection. Alzheimer disease (AD)2 is a debilitating illness of the brain defined by the progressive deterioration of cognition and memory as a result of selective neuronal loss in the hippocampus and surrounding areas of the cerebral cortex (1). There is substantial evidence to suggest that at least a subset of neurons in the AD brain die by apoptosis (2). The principal neuropathological hallmark of the disease, ␤-amyloid peptide (A␤), has been shown to induce apoptosis in neuronal cells in vivo and in vitro (3, 4) through a variety of enzymatic pathways that include activation of caspase-3 (5), calpain (6, 7), and lysosomal cathepsins (8, 9).Recently, the lysosomal system has been implicated in AD pathogenesis (9, 10). Neurons of AD patients demonstrate alterations in the lysosomal system, including the cellular pathways that converge on it, namely endocytosis and autophagy (10, 11). Such alterations include an increase in the size and number of endosomes (10, 12), autophagosomes (13) and lysosomes (10) and an increase in the gene expression and synthesis of all classes of lysosomal hydrolases, including cathepsins (14). In addition to their role in the digestion of cellular waste, it has become clear that partial and selective lysosomal membrane permeabilization (LMP), followed by the release of lysosomal enzymes into the cytosol, can induce apoptotic cell death (15). Cathepsins D and L are among the lysosomal proteases that have been implicated in apoptosis by virtue of their ability to activate apoptotic effectors, such as mitochondrial uncoupling and caspases (16).Among the agents that are ca...

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Section: Discussionsupporting

confidence: 91%

Endocannabinoids Prevent β-Amyloid-mediated Lysosomal Destabilization in Cultured Neurons

Noonan

Tanveer

Klompas

et al. 2010

Journal of Biological Chemistry

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“…We found that brain glioma cell growth inhibited by embelin was associated with apoptosis. Joy et al (27) found that embelin arrested the cell cycle of colon cancer cells at phase G1 via downregulation of the p21 gene. Our findings are fundamentally identical to theirs.…”

Section: Discussionmentioning

confidence: 99%

Embelin-induced brain glioma cell apoptosis and cell cycle arrest via the mitochondrial pathway

Wang

Zhang

et al. 2013

Oncology Reports

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Abstract. Brain glioma is the most common malignant intracranial tumor and has become the focus of research on diseases of the central nervous system due to its high incidence and poor prognosis. As a small-molecule inhibitor of X-linked inhibitor of apoptosis protein (XIAP), embelin has the ability to specifically inhibit XIAP to control and regulate the apoptosis of various types of tumor cells. However, to date, the mechanism of action for this effect is not well understood. The aim of this study was to investigate the role that the mitochondrial pathway plays in embelin-induced brain glioma cell apoptosis and the effect of embelin on the cell cycle. Brain glioma cells were treated with different doses of embelin. The MTT method

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“…For example, in myeloid leukemia cells, the activation of temperature-sensitive p53 is sufficient to cause LMP that precedes MOMP (Yuan et al, 2002). Furthermore, early LMP in TNF-treated fibrosarcoma cells (Li et al, 2007), embelin-treated colon cancer cells (Joy et al, 2010), as well as in cortical neurons exposed to D9-tetrahydrocannabinol or b-amyloid (Fogarty et al, 2010;Gowran and Campbell, 2008) depends on p53 and is associated with the localization of phospho-Ser15-p53 to the lysosomal membrane. The recruitment of phosphoSer15-p53 to the lysosomes depends on LAPF (LMP-inducing lysosome-associated apoptosis-inducing protein containing PH and FYVE domains) (Li et al, 2007).…”

Section: P53mentioning

confidence: 99%

Lysosomal cell death at a glance

Aits

Jäättelä

2013

Journal of Cell Science

529

453

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Summary Lysosomes serve as the cellular recycling centre and are filled with numerous hydrolases that can degrade most cellular macromolecules. Lysosomal membrane permeabilization and the consequent leakage of the lysosomal content into the cytosol leads to so-called “lysosomal cell death”. This form of cell death is mainly carried out by the lysosomal cathepsin proteases and can have necrotic, apoptotic or apoptosis-like features depending on the extent of the leakage and the cellular context. This article summarizes our current knowledge on lysosomal cell death with an emphasis on the upstream mechanisms that lead to lysosomal membrane permeabilization.

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Lysosomal destabilization and cathepsin B contributes for cytochrome c release and caspase activation in embelin‐induced apoptosis

Cited by 49 publications

References 32 publications

Endocannabinoids Prevent β-Amyloid-mediated Lysosomal Destabilization in Cultured Neurons

Endocannabinoids Prevent β-Amyloid-mediated Lysosomal Destabilization in Cultured Neurons

Embelin-induced brain glioma cell apoptosis and cell cycle arrest via the mitochondrial pathway

Lysosomal cell death at a glance

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