Participation of Cathepsins B and D in Apoptosis of PC12 Cells Following Serum Deprivation

Shibata, Masahiro; Kanamori, Shiro; Isahara, Kyoko; Ohsawa, Yoshiyuki; Konishi, Akio; Kametaka, Satoshi; Watanabe, Tsuyoshi; Ebisu, Shigeyuki; Ishido, Kazumi; Kominami, Eiki; Uchiyama, Yasuo

doi:10.1006/bbrc.1998.9422

Cited by 110 publications

(72 citation statements)

References 26 publications

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“…100 In transgenic models overexpression of cathepsin D induced or sensitised HeLa and PC12 cells to apoptosis upon serum deprivation. 101 Other lysosomal cysteine proteases such as cathepsin B,C,L have been implicated in caspase activation as well. 97,102,103 In particular, in cell free systems purified cathepsin B has been found to directly cleave caspase zymogens: it readily cleaved Figure 3 Potential roles of lysosomes in cell death.…”

Section: Lysosomes In Cell Deathmentioning

confidence: 99%

The autophagosomal–lysosomal compartment in programmed cell death

2001

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In the last decade a tremendous progress has been achieved in understanding the control of apoptosis by survival and death factors as well as the molecular mechanisms of preparation and execution of the cell's suicide. However, accumulating evidence suggests that programmed cell death (PCD) is not confined to apoptosis but that cells use different pathways for active self-destruction as reflected by different morphology: condensation prominent, type I or apoptosis; autophagy prominent, type II; etc. Autophagic PCD appears to be a phylogenetically old phenomenon, it may occur in physiological and disease states. Recently, distinct biochemical and molecular features have been be assigned to this type of PCD. However, autophagic and apoptotic PCD should not be considered as mutually exclusive phenomena. Rather, they appear to reflect a high degree of flexibility in a cell's response to changes of environmental conditions, both physiological or pathological. Furthermore, recent data suggest that diverse or relatively unspecific signals such as photodamage or lysosomotropic agents may be mediatd by lysosomal cysteine proteases (cathepsins) to caspases and thus, apoptosis. The present paper reviews morphological, functional and biochemical/molecular data suggesting the participation of the autophagosomal ± lysosomal compartment in programmed cell death. Cell Death and Differentiation (2001) 8, 569 ± 581.

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Section: Lysosomes In Cell Deathmentioning

confidence: 99%

The autophagosomal–lysosomal compartment in programmed cell death

2001

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“…The therapy may have failed due to the high levels of cathepsin L, which may protect tumors from chemotherapeutically induced apoptosis. In analogy to cathepsin L, increased expression of cathepsin B rescued cells from apoptotic death induced by serum deprivation, 40 whereas transfection with antisense oligonucleotides of cathepsin B induced apoptosis. 41 In contrast, some studies have suggested that cathepsin B, calpain, granzyme B (a serine protease), and aspartic protease cathepsin D stimulated apoptosis.…”

Section: Cancer Gene Therapymentioning

confidence: 99%

Selective suppression of cathepsin L by antisense cDNA impairs human brain tumor cell invasion in vitro and promotes apoptosis

et al. 2003

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Invasion and metastasis of certain tumors are accompanied by increased mRNA protein levels and enzymatic activity of cathepsin L. Cathepsin L has also been suggested to play a role in the proteolytic cascades associated with apoptosis. To investigate the role of cathepsin L in brain tumor invasion and apoptosis, the human glioma cell line, IPTP, was stably transfected with full -length antisense and sense cDNA of cathepsin L. Down -regulation of cathepsin L by antisense cDNA significantly impaired ( up to 70% ) glioma cell invasion in vitro and markedly increased glioma cell apoptosis induced by staurosporine. Compared to control and parental cell lines, antisense down -regulation of cathepsin L was associated with an earlier induction of caspase -3 activity. Up -regulation of cathepsin L activity by sense cDNA was associated with reduced apoptosis and later induction of caspase -3 activity. Moreover, down -regulation of cathepsin L lowered the expression of antiapoptotic protein Bcl -2, whereas up -regulation increased the expression of Bcl -2, indicating that cathepsin L acts upstream of caspase -3. These data show that cathepsin L is an important protein mediating the malignancy of gliomas and its inhibition may diminish their invasion and lead to increased tumor cell apoptosis by reducing apoptotic threshold.

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“…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%

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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Participation of Cathepsins B and D in Apoptosis of PC12 Cells Following Serum Deprivation

Cited by 110 publications

References 26 publications

The autophagosomal–lysosomal compartment in programmed cell death

The autophagosomal–lysosomal compartment in programmed cell death

Selective suppression of cathepsin L by antisense cDNA impairs human brain tumor cell invasion in vitro and promotes apoptosis

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

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