Cathepsin B contributes to TNF-α–mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c

Guicciardi, Maria Eugenia; Deussing, Jan M.; Miyoshi, Hideyuki; Bronk, Steven F.; Svingen, Phyllis A.; Peters, Christoph; Kaufmann, Scott H.; Gores, Gregory J.

doi:10.1172/jci9914

Cited by 661 publications

(697 citation statements)

References 66 publications

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“…5,8,9 Why should inhibition of just one cathepsin be detrimental for NB cell survival? It has been previously shown that deficiency of CD or inhibition of either CD or CB does not compromise overall turnover of long-lived proteins.…”

Section: Discussionmentioning

confidence: 99%

“…3,4 Recently, proteases resident within the endosomal-lysosomal compartment (cathepsins) have also been associated with apoptosis. [5][6][7][8][9] These studies demonstrated the need for a cathepsin-mediated proteolytic event in the apoptotic pathway triggered by cytokines or antiblastic drugs. In addition, the active participation of the autophagic proteolytic pathway, particularly of lysosomal cathepsins B and D (CB, CD), has been envisaged in rat pheochromocytoma PC12 cell death after nutrient and serum factor deprivation.…”

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confidence: 93%

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Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas

Castino¹,

Pace²,

Démoz³

et al. 2001

Intl Journal of Cancer

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Neuroblastoma is the most common type of cancer in infants. In children this tumor is particularly aggressive; despite various new therapeutic approaches, it is associated with poor prognosis. Given the importance of endosomallysosomal proteolysis in cellular metabolism, we hypothesized that inhibition of lysosomal protease would impact negatively on neuroblastoma cell survival. Treatment with E-64 or CA074Me (2 specific inhibitors of cathepsin B) or with pepstatin A (a specific inhibitor of cathepsin D) was cytotoxic for 2 neuroblastoma cell lines having different degrees of malignancy. Cell death was associated with condensation and fragmentation of chromatin and externalization of plasma membrane phosphatidylserine, 2 hallmarks of apoptosis. Concomitant inhibition of the caspase cascade protected neuroblastoma cells from cathepsin inhibitor-induced cytotoxicity. These data indicate that prolonged inhibition of the lysosomal proteolytic pathway is incompatible with cell survival, leading to apoptosis of neuroblastoma cells, and that the cathepsin-mediated and caspase-mediated proteolytic systems are connected and cooperate in the regulation of such an event. Since modern antitumor chemotherapy is aimed at restoring the normal rate of apoptosis in neoplastic tissues, the demonstration that endosomal-lysosomal cathepsins are involved in this process may constitute a basis for novel strategies that include cathepsin inhibitors in the therapeutic regimen. © 2002 Wiley-Liss, Inc. Key words: apoptosis; neuroblastoma; caspases; cathepsins; protease inhibitorsAltered regulation of cell survival and death, including apoptosis, is considered an important factor in tumor development and progression, as well as in the response to antineoplastic therapy. 1,2 The molecular pathways controlling apoptosis include a complex network of intracellular proteases that act in an orderly sequence on cellular substrates and lead to characteristic modifications of cell morphology with eventual DNA cleavage and apoptotic body formation. Several proteolytic systems have been shown to participate in the apoptotic process, depending on the cell type and stimuli adopted. With few exceptions, the caspase system seems to be the most universally involved one. 3,4 Recently, proteases resident within the endosomal-lysosomal compartment (cathepsins) have also been associated with apoptosis. 5-9 These studies demonstrated the need for a cathepsin-mediated proteolytic event in the apoptotic pathway triggered by cytokines or antiblastic drugs. In addition, the active participation of the autophagic proteolytic pathway, particularly of lysosomal cathepsins B and D (CB, CD), has been envisaged in rat pheochromocytoma PC12 cell death after nutrient and serum factor deprivation. In this model of caspasedependent apoptosis, CD acted as a death factor, whereas CB acted as a pro-survival factor. 10 We followed an opposite approach, assuming that the endosomal-lysosomal proteolytic pathway serves crucial functions for cell viability. Indeed, experiments usi...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 93%

Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas

Castino¹,

Pace²,

Démoz³

et al. 2001

Intl Journal of Cancer

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“…[2][3][4] Lysosomal cathepsins including cathepsins B, D, and L translocate from the lysosomal lumen to the cytosol in response to a variety of signals such as TNF receptor ligation, 5,6 p53 activation, 7 oxidative stress, 8 and the lipid second messenger sphingosine. 9 Such a translocation can also be induced by lysosomotropic agents such as cyprofloxacin, norfloxacin, and hydroxychloroquine.…”

Section: Lysosomes As Death Signal Integratorsmentioning

confidence: 99%

“…10,11 Thus, several cathepsins (and perhaps even other lysosomal hydrolases) may be able to constitute the link between LMP and MMP. Indeed, cysteine cathepsins B, H, L, S, and K have recently been shown to cleave and activate the Bax-activating Bcl-2 family member, Bid, in vitro (Boris Turk, personal communication), and the TNF-induced MMP in hepatocytes depends on the activity of cathepsin B rather than cathepsin D. 5 Such variations in the requirement of individual cathepsins between the diverse apoptosis models may reflect differences in the expression levels of cathepsins themselves or their endogenous cathepsin inhibitors, which are highly cell type dependent. No signs of cathepsin D-mediated cleavage of either Bid or Bax were readily detectable in staurosporinetreated activated T cells.…”

Section: Missing Links Between Lysosomes and Mitochondriamentioning

confidence: 99%

Lysosomes and mitochondria in the commitment to apoptosis: a potential role for cathepsin D and AIF

2003

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“…1,2 In addition to the traditional apoptotic process mediated by caspases, other proteases such as the cathepsin cysteine proteases have been shown to participate in apoptotic signaling. [3][4][5][6][7][8][9][10][11][12][13][14] Although cathepsins normally reside in the lysosome and carry out nonselective degradation of proteins, a strong case was made for the involvement of these proteases in apoptosis when it was shown that agents that disrupted lysosomes and caused cathepsins to redistribute to the cytoplasm inevitably resulted in apoptosis. 13,[15][16][17][18][19] Similarly, cathepsin inhibitor treatment blocked this apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis caused by cathepsins does not require Bid signaling in an in vivo model of progressive myoclonus epilepsy (EPM1)

Vilaythong

Yin

et al. 2003

Cell Death Differ

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Apoptosis can be mediated by mechanisms other than the traditional caspase-mediated cleavage cascade. There is growing recognition that alternative proteolytic enzymes such as the lysosomal cathepsin proteases can initiate or propagate proapoptotic signals, but it is currently unclear how cathepsins achieve these actions. Recent in vitro evidence suggests that cathepsins cleave the proapoptotic Bcl-2 family member Bid, thereby activating it and allowing it to induce the mitochondrial release of cytochrome c and subsequent apoptosis. We have tested this hypothesis in vivo by breeding mice that lack cathepsin inhibition (cystatin B-deficient mice) to Bid-deficient mice, to determine whether the apoptosis caused by cathepsins is dependent on Bid signaling. We found that cathepsins are still able to promote apoptosis even in the absence of Bid, indicating that these proteases mediate apoptosis via a different pathway, or that some other molecule can functionally substitute for Bid in this system.

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Cathepsin B contributes to TNF-α–mediated hepatocyte apoptosis by promoting mitochondrial release of cytochrome c

Cited by 661 publications

References 66 publications

Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas

Lysosomal proteases as potential targets for the induction of apoptotic cell death in human neuroblastomas

Lysosomes and mitochondria in the commitment to apoptosis: a potential role for cathepsin D and AIF

Apoptosis caused by cathepsins does not require Bid signaling in an in vivo model of progressive myoclonus epilepsy (EPM1)

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