Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple types of degradative enzymes, including cathepsins of the cysteine protease family, have been implicated in the regulation of angiogenesis and invasion during cancer progression. Several cysteine cathepsins are up-regulated in a mouse model of pancreatic islet cell carcinogenesis (RIP1-Tag2), and tumor progression is impaired following their collective pharmacologic inhibition. Using null mutations of four of the implicated cysteine cathepsins, we have now dissected their individual roles in cancer development. Mutants of cathepsins B or S impaired tumor formation and angiogenesis, while cathepsin B or L knockouts retarded cell proliferation and tumor growth. Absence of any one of these three genes impaired tumor invasion. In contrast, removal of cathepsin C had no effect on either tumor formation or progression. We have identified E-cadherin as a target substrate of cathepsins B, L, and S, but not cathepsin C, potentially explaining their differential effects on tumor invasion. Furthermore, we detected analogous increases in cathepsin expression in human pancreatic endocrine neoplasms, and a significant association between increased levels of cathepsins B and L and tumor malignancy. Thus individual cysteine cathepsin genes make distinctive contributions to tumorigenesis.
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PMID:Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. 1648 67

Cysteine cathepsins are lysosomal peptidases involved in the regulation of innate and adaptive immune responses. Among the diverse processes, regulation of granule-dependent cytotoxicity of cytotoxic T-lymphocytes (CTLs) and natural killer (NK) cells during cancer progression has recently gained significant attention. The function of cysteine cathepsins is regulated by endogenous cysteine protease inhibitors-cystatins. Whereas other cystatins are generally cytosolic or extracellular proteins, cystatin F is present in endosomes and lysosomes and is thus able to regulate the activity of its target directly. It is delivered to endosomal/lysosomal vesicles as an inactive, disulphide-linked dimer. Proteolytic cleavage of its N-terminal part leads to the monomer, the only form that is a potent inhibitor of cathepsins C, H and L, involved in the activation of granzymes and perforin. In NK cells and CTLs the levels of active cathepsin C and of granzyme B are dependent on the concentration of monomeric, active cystatin F. In tumour microenvironment, inactive dimeric cystatin F can be secreted from tumour cells or immune cells and further taken up by the cytotoxic cells. Subsequent monomerization and inhibition of cysteine cathepsins within the endosomal/lysosomal vesicles impairs granzyme and perforin activation, and provokes cell anergy. Further, the glycosylation pattern has been shown to be important in controlling secretion of cystatin F from target cells, as well as internalization by cytotoxic cells and trafficking to endosomal/lysosomal vesicles. Cystatin F is therefore an important mediator used by bystander cells to reduce NK and T-cell cytotoxicity.
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PMID:Cystatin F as a regulator of immune cell cytotoxicity. 2974 98

Cathepsins are lysosomal acid hydrolases that make crucial contributions to tumor progression through a variety of signaling mechanisms, including autophagy, cell survival, chemotherapeutic resistance, and metastasis. Herein, we report that cathepsin C (CTSC) silencing upregulates the anticancer potential of curcumin in colorectal cancer cells (CRCs) both in vitro and in athymic mice xenografts. Curcumin treatment enhances CTSC level in CRCs; however, CTSC silencing with subsequent curcumin treatment (sequential treatment) induces ER stress and autophagic dysregulation accompanied by lysosomal permeabilization and ROS generation. This lysosomal permeabilization triggered the cytosolic CTSB mediated BID-dependent mitochondrial membrane permeabilization and thereby caspase-dependent apoptosis. This phenotype can be rescued by CTSB inhibition and NAC, which further supported the involvement of ROS and CTSB in apoptosis following sequential treatment. Indeed, the sequential CTSC silencing and curcumin treatment also significantly curtailed tumor volume as well as ameliorated cytosolic cyt c and tBID protein levels in tumor tissues compared to those in control and individual treatments of CTSC targeting and on curcumin treatment in nude mice xenografts. The results reveal that CTSC can controls the curcumin-induced cytotoxic insult through autophagy maintenance both in vitro and in athymic mice xenografts, thereby providing an insight into the role of CTSC in chemoprevention of CRCs.
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PMID:In vitro and in vivo studies on potentiation of curcumin-induced lysosomal-dependent apoptosis upon silencing of cathepsin C in colorectal cancer cells. 3283 67