Involvement of cathepsin D in chemotherapy-induced cytochrome c release, caspase activation, and cell death

Abstract

Treatment of cells with chemotherapy drugs activates the intrinsic mitochondrial pathway of apoptosis and the caspase protease cascade. Recently, the lysosomal protease cathepsin D has been implicated in apoptosis caused by oxidative stress, inhibition of protein kinase C, and stimulation of the TNFR1 and Fas death receptors.

Overexpression of both catalytically active and -inactive cathepsin D by cancer cells enhances apoptosis-dependent chemo-sensitivity

“…It is therefore open to question whether cath-D might be able to cleave cytosolic substrate(s) implicated in the apoptotic cascade. In accordance with this proposal, it was recently described that pepstatin A did not prevent the death of cells treated by etoposide, doxorubicin, anti-CD95 or TNF-alpha (Demoz et al, 2002;Tardy et al, 2003;Emert-Sedlak et al, 2005). Furthermore, pepstatin A did not suppress Bid cleavage or procaspases-9 and -3 activation by photodynamic therapy in murine hepatoma cells (Reiners et al, 2002).…”

“…More recently, cath-D has also been discovered as a key mediator of apoptosis induced by many apoptotic agents such as IFN-gamma, Fas/APO, TNF-alpha (Deiss et al, 1996), oxidative stress (Roberg and Ö llinger, 1998;Ö llinger, 2000;Kagedal et al, 2001;Roberg, 2001;Takuma et al, 2003), adriamycin and etoposide (Wu et al, 1998;Emert-Sedlak et al, 2005), as well as staurosporine (Johansson et al, 2003). The role of cath-D in apoptosis has been linked to the lysosomal release of mature 34 kDa cath-D into the cytosol leading in turn to the mitochondrial release of cytochrome c (cyt c) into the cytosol (Roberg and Ö llinger, 1998;Ö llinger, 2000;Kagedal et al, 2001;Roberg, 2001;Roberg et al, 2002;Johansson et al, 2003), activation of pro-caspases (Ö llinger, 2000;Roberg et al, 2002;Johansson et al, 2003;Heinrich et al, 2004), in vitro cleavage of Bid at pH 6.2 (Heinrich et al, 2004), or Bax activation independently of Bid cleavage (Bide`re et al, 2003).…”

ATG7 deficiency suppresses apoptosis and cell death induced by lysosomal photodamage

“…36 In each of these studies, proapoptotic concentrations of the different toxicants induced an autophagic response in wild-type cultures that preceded or paralleled the initiation of apoptosis. Although analyses of autophagic flux were not reported in these studies, it is worth noting that apoptotic concentrations of etoposide, 37 induce endosomal/lysosomal permeabilization or rupture in a variety of cellular systems. In doing so, the effects of these agents on lysosomes may be analogous to lysosomal photosensitizers, and contribute to autophagosome accumulation and the development of autophagic stress.…”

Cathepsin D—Many functions of one aspartic protease

“…While some studies reported that CD can directly induce apoptosis [118][119][120], many studies demonstrated that CD is a mediator of apoptosis induced by several stimuli, such as staurosporine, IFN-gamma, Fas/CD95/APO-1, TNF, etoposide, 5-fluorouracil, cisplatin [118,121,122], adriamycin [122], resveratrol [123], doxorubicin [124], growth factor deprivation [125], oxidative stress [109,126,127], and sphingosine [113]. These data suggests that CD promote apoptosis induced by cytotoxic and stress agents.…”

“…It has been shown that higher doses of pepstatin A inhibit MAPK signaling [133]. In a similar fashion, pharmacological inhibitors of caspases have been shown to nonspecifically inhibit cathepsins, raising the possibility that the role of cathepsins may have been overlooked in defining many "caspase-dependent" processes [121,134]. The design, synthesis and use of new specific CD inhibitors is therefore of great interest and may have important research and therapeutical consequences [19,135].…”