Cysteine cathepsin proteases as pharmacological targets in cancer

Palermo, Carmela; Joyce, Johanna A.

doi:10.1016/j.tips.2007.10.011

Cited by 271 publications

(226 citation statements)

References 59 publications

Supporting

Mentioning

221

Contrasting

Unclassified

Order By: Relevance

“…These functional aspects of the proteases remain to be elucidated, however, because our genetic approach does not allow us to distinguish between the proteolytic and nonproteolytic features of Ctsz or the endopeptidase and exopeptidase activities of Ctsb. Cysteine cathepsins have been the focus of clinical investigations as potential targets for cancer therapy (43). In this regard, our data on reciprocal functional compensation of Ctsb and Ctsz single deficiencies in tumor promotion and the efficacy of their combined knockout suggest to test a therapeutic strategy using a combination of selective inhibitors for both proteases.…”

Section: Discussionmentioning

confidence: 91%

Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice

Sevenich

Schurigt

Sachse

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

153

122

View full text Add to dashboard Cite

The lysosomal cysteine proteases cathepsin B (Ctsb) and cathepsin Z (Ctsz, also called cathepsin X/P) have been implicated in cancer pathogenesis. Compensation of Ctsb by Ctsz in Ctsb −/− mice has been suggested. To further define the functional interplay of these proteases in the context of cancer, we generated Ctsz null mice, crossed them with Ctsb-deficient mice harboring a transgene for the mammary duct–specific expression of polyoma middle T oncogene (PymT), and analyzed the effects of single and combined Ctsb and Ctsz deficiencies on breast cancer progression. Single Ctsb deficiency resulted in delayed detection of first tumors and reduced tumor burden, whereas Ctsz-deficient mice had only a prolonged tumor-free period. However, only a trend toward reduced metastatic burden without statistical significance was detected in both single mutants. Strikingly, combined loss of Ctsb and Ctsz led to additive effects, resulting in significant and prominent delay of early and advanced tumor development, improved histopathologic tumor grading, as well as a 70% reduction in the number of lung metastases and an 80% reduction in the size of these metastases. We conclude that the double deficiency of Ctsb and Ctsz exerts significant synergistic anticancer effects, whereas the single deficiencies demonstrate at least partial reciprocal compensation.

show abstract

Section: Discussionmentioning

confidence: 91%

Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice

Sevenich

Schurigt

Sachse

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

153

122

View full text Add to dashboard Cite

show abstract

“…Because cysteine cathepsins are broadly up-regulated in cancer, there has been an interest to pharmacologically target them for the treatment of malignancies. 51 A notable target among these proteases is cathepsin B, a protease implicated in apoptosis via its cleavage-activating capacity aimed at Bcl-2 family members, resulting in disruption of the mitochondrial membrane and cytochrome c release. 52 Before our study no equivalent downstream substrate for cathepsin B in the autophagy process had been identified.…”

Section: Discussionmentioning

confidence: 99%

Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide

Goussetis

Gounaris

et al. 2012

Blood

117

View full text Add to dashboard Cite

We provide evidence that arsenic trioxide (As 2 O 3 ) targets the BCR-ABL oncoprotein via a novel mechanism involving p62/ SQSTM1-mediated localization of the oncoprotein to the autolysosomes and subsequent degradation mediated by the protease cathepsin B. Our studies demonstrate that inhibitors of autophagy or ca- IntroductionElements of the autophagic machinery have attracted recently considerable attention as a potential target for the development of novel approaches for the treatment of malignancies. 1,2 Similar to apoptosis, autophagy is a programmed cell death mechanism, but it is distinguished by a self-catabolic process involving lysosomal proteolytic degradation of cellular components. 3 This is initiated by the formation of a double-membrane enclosed structure, known as the autophagosome. 4 On fusion with a lysosome, a cellular organelle characterized by low pH and hydrolytic enzymes, 5,6 such structure eventually develops into the autophagolysosome where degradation of organelles occurs.Under different circumstances, autophagy can either inhibit or promote malignant cell survival, but its precise role in tumorigenesis remains to be established. 7,8 The role of inducible autophagy in BCR-ABL expressing leukemia cells is poorly understood. For example, there is previous evidence suggesting that autophagy may play regulatory roles in BCR-ABL leukemogenesis, 9 whereas other studies have shown that pharmacologic inhibition of autophagy enhances the effects of imatinib mesylate and other targeted therapies in CML. [10][11][12] There are also opposing lines of evidence, pointing toward tumor inhibitory effects of autophagy, 13,14 although a recent study demonstrated that BCR-ABL exerts suppressive effects on autophagy via engagement of the PI3K/FoxO4/ATF5/ mTOR pathway. 15 Arsenic trioxide (AS 2 O 3 ) exhibits potent antileukemic effects in vitro and in vivo and has major clinical activity in the treatment of patients with acute promyelocytic leukemia (APL). [16][17][18] This agent was previously shown to target and eliminate leukemia initiating stem cells (LICs) in mouse models in vivo via PML targeting. 19 Notably, there is evidence that AS 2 O 3 degrades BCR-ABL, 20 raising the possibility that this agent may provide an approach to target CML LICs. However, a major limiting factor for the incorporation of arsenic in non-APL malignancies has been the requirement of high concentrations for induction of cell death in non-APL cells and the incomplete understanding of the mechanisms by which it promotes antileukemic responses.A major mechanism contributing to the antineoplastic effects of arsenic is induction of apoptosis, 16-18 with upstream JNK activation being a prominent regulatory mechanism. 21 In a recent study, we provided evidence that arsenic trioxide induces autophagy in AML leukemic progenitors and demonstrated that such autophagy is essential for generation of the inhibitory effects of arsenic on primitive leukemic precursors. 22 However, the key downstream cellular events by which such arsenic-de...

show abstract

“…Cathepsins are often upregulated in human cancers and their high levels of expression have been correlated with an increased risk of relapse and poor prognosis (GyrdHansen et al, 2004;Palermo and Joyce, 2008). Cathepsins contribute to distinct tumorigenic processes such as angiogenesis, metastasis and invasion, and these functions are attributed to the extracellular actions of cathepsins once they have been released from secretory lysosomes (Palermo and Joyce, 2008).…”

Section: Lmp In Cancer Cellsmentioning

confidence: 99%

“…Cathepsins contribute to distinct tumorigenic processes such as angiogenesis, metastasis and invasion, and these functions are attributed to the extracellular actions of cathepsins once they have been released from secretory lysosomes (Palermo and Joyce, 2008). Thus, cathepsins participate in the degradation of basement membranes and extracellular matrix, thereby facilitating tumor invasion and metastasis (Tardy et al, 2006).…”

Section: Lmp In Cancer Cellsmentioning

confidence: 99%

Lysosomal membrane permeabilization in cell death

2008

View full text Add to dashboard Cite

Mitochondrial outer membrane permeabilization (MOMP) constitutes one of the major checkpoint(s) of apoptotic and necrotic cell death. Recently, the permeabilization of yet another organelle, the lysosome, has been shown to initiate a cell death pathway, in specific circumstances. Lysosomal membrane permeabilization (LMP) causes the release of cathepsins and other hydrolases from the lysosomal lumen to the cytosol. LMP is induced by a plethora of distinct stimuli including reactive oxygen species, lysosomotropic compounds with detergent activity, as well as some endogenous cell death effectors such as Bax. LMP is a potentially lethal event because the ectopic presence of lysosomal proteases in the cytosol causes digestion of vital proteins and the activation of additional hydrolases including caspases. This latter process is usually mediated indirectly, through a cascade in which LMP causes the proteolytic activation of Bid (which is cleaved by the two lysosomal cathepsins B and D), which then induces MOMP, resulting in cytochrome c release and apoptosome-dependent caspase activation. However, massive LMP often results in cell death without caspase activation; this cell death may adopt a subapoptotic or necrotic appearance. The regulation of LMP is perturbed in cancer cells, suggesting that specific strategies for LMP induction might lead to novel therapeutic avenues.

show abstract

Cysteine cathepsin proteases as pharmacological targets in cancer

Cited by 271 publications

References 59 publications

Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice

Synergistic antitumor effects of combined cathepsin B and cathepsin Z deficiencies on breast cancer progression and metastasis in mice

Autophagic degradation of the BCR-ABL oncoprotein and generation of antileukemic responses by arsenic trioxide

Lysosomal membrane permeabilization in cell death

Contact Info

Product

Resources

About