Function of cath-D in apoptosis

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Cysteine and aspartic cathepsins play key roles in tumor cell death via the mediation of apoptosis [4, 11, 49-51]. The function of cath-D in apoptosis needs further investigation, since this protease has both anti-apoptotic and pro-apoptotic functions.

Anti-apoptotic characteristics of cath-D

Even though cath-D gene expression outlines the areas of physiological cell death during embryo development [52], cath-D deficiency in mice has revealed its anti-apoptotic function under physiological conditions [35-37]. Indeed, cath-D knock-out mice developed apoptosis in the thymus and in the retina [35-37].  Some other studies have also suggested that cath-D may have an anti-apoptotic role in cancer. Our own immunohistochemical studies have revealed that xenografts of cancer cells overexpressing cath-D displayed less tumor apoptosis than mock-transfected cancer cells [53]. More recently, cath-D has been shown to protect human neuroblastoma cells from doxorubicin-induced cell death [54].

Pro-apoptotic characteristics of cath-D

Cath-D is a key mediator of induced-apoptosis, and its proteolytic activity has often been shown to be involved in this event [49, 55-63]. During apoptosis, mature lysosomal cath-D is translocated to the cytosol due to lysosomal membrane permeabilization (LMP) [56-58, 60, 64, 65]. Cytoplasmic cath-D has been shown to cleave Bid to form tBid [66, 67], which triggers the insertion of Bax into the mitochondrial membrane [62, 68], and leads in turn to the mitochondrial release of cytochrome c into the cytosol, and the activation of pro-caspases 9 and 3 [56, 60, 64, 66]. Cath-D is also involved in caspase-independent apoptosis by activating Bax independently of Bid cleavage, and leading in turn to the mitochondrial release of the apoptosis inducing factor (AIF) [68]. More recently, it has been shown that cath-D can also activate pro-caspase 8, initiating neutrophil apoptosis during the resolution of inflammation [69]. Interestingly, a recent report indicates the presence of mature cath-D in the nucleus during cell death [70], and it has been proposed that nuclear cath-D may mediate the proteolytic activation of endonuclease 23 during cryonecrotic cell death [71].

Since cath-D is one of the lysosomal enzymes that requires a more acidic pH to be proteolytically-active than lysosomal cysteine enzymes, such as cath-B and cath-L, it is open to question whether cytosolic cath-D is able to cleave the substrate(s) implicated in the apoptotic cascade. In some studies, pepstatin A, an inhibitor of the enzyme, partially delayed the apoptosis induced by IFN-gamma and FAS/APO [55], staurosporin [60, 68], TNF-alpha [55, 66, 72], serum deprivation [73], oxidative stress [56, 57, 59], or when pepstatin A was co-micro-injected with cath-D [64]. Other studies indicate that the effect of a mutant cath-D deprived of catalytic activity was indistinguishable from that of the normal enzyme [61, 74]. Furthermore, microinjection of the inactive precursor pro-cath-D into cytosol confirmed that the pro-apoptotic effect of cytosolic cath-D may be also independent of its catalytic activity [75]. In conclusion, cath‑D can promote apoptosis by mechanisms that may be dependent on and/or independent of its active site.