Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ascitic fluid of a patient with colon cancer was found to contain an inactive cathepsin B-like enzyme. The inactive enzyme with a molecular weight of 40 kDa was converted by pepsin treatment into an active form with a molecular weight of 28 kDa as revealed by Sephadex G-75 gel chromatography. The inactive cathepsin B-like enzyme was considered to represent a precursor form and not an enzyme-inhibitor complex. The activated cathepsin B-like enzyme resembled human liver cathepsin B in its enzymatic characteristics. Cysteine proteinase inhibitor activity was also detected in the same ascitic fluid, and it was separated into two main forms by Sephadex G-75 gel chromatography. The high molecular weight inhibitor fractions reacted with antiserum against alpha-CPI and the low molecular weight fractions reacted with antiserum against cystatin B.
 ...
PMID:An inactive cathepsin B-like enzyme and cysteine proteinase inhibitors in colon cancer ascites. 152 7

Activities of cathepsin B, cathepsin L, and plasminogen activators (urinary type plasminogen activator and tissue type plasminogen activator) were assayed in homogenates of cancer tissue, normal tissue closely surrounding the cancer tissue, and normal tissue distant from the cancer tissue from 30 patients undergoing surgery for gastric cancers and 10 patients undergoing surgery for colon cancers. Activities of those proteases were also assayed in homogenates of adenoma tissue from 10 patients undergoing polypectomy for colon polyps. In the gastric cancer tissue homogenates, the activities of cathepsin B, cathepsin L and tissue type plasminogen activator were significantly higher than in normal tissues. By contrast, the activities of urinary type plasminogen activator of gastric cancer tissues were significantly lower than normal tissues. In the colon cancer tissue homogenates, the activities of cathepsin, B, cathepsin L, and urinary type plasminogen activator were significantly higher than in normal tissues. On the other hand, the activities of tissue type plasminogen activator of cancer tissues were significantly lower than normal tissues. But there were no significant differences in the activities of plasminogen activators between the cancer tissues and adenoma tissues. These results suggest that cathepsin B and cathepsin L play an important role in gastric and colon cancer proliferation and evolution, although the roles of plasminogen activators in gastric and colon cancer proliferation and evolution and in the colon adenoma-carcinoma sequence are still unknown.
 ...
PMID:[Protease activities in gastric and colon cancer tissues]. 223 1

Gelatinase A (MMP-2) and cathepsin B are proteinases which have been proposed to participate in human tumor invasion and metastasis. Precise quantitation of the activity of these enzymes in invading tumors has not been previously described. We utilized a novel tissue microdissection technique to determine levels of enzyme activity in specific microscopic areas of invasive human colon cancer. Tissue specimens smaller than one high power field can be extracted from the samples and analyzed. Increased levels of pro-enzyme and active enzyme forms of gelatinase A (MMP-2) and increased cathepsin B activity were localized in regions of tumor invasion as compared with a matched number of normal epithelial cells from the same patient. Levels of progelatinase B (MMP-9) were also increased in the tumors; however, we did not observe activation of this enzyme. To investigate the mechanism of gelatinase A activation, we amplified DNA of specific microdissected tumor cell populations using polymerase chain reaction. We did not detect a mutation in the activation locus of the enzyme in any of the tumors studied, which suggests that activation may be due to up-regulation of a tumor-associated gelatinase A activating species. Microdissection of frozen tissue sections may prove valuable in the study of proteinases in human tumor invasion as well as in the detection of genetic alterations in human cancers.
 ...
PMID:Increased gelatinase A (MMP-2) and cathepsin B activity in invasive tumor regions of human colon cancer samples. 799 33

Colon carcinomas commonly contain mutations in Ki-ras4B, but very rarely in Ha-ras, suggesting that different Ras isoforms may have distinct functions in colon epithelial cell biology. In an earlier study we had demonstrated that oncogenic Ki-ras4BVal-12, but not oncogenic Ha-rasVal-12, blocks the apicobasal polarization of colon epithelial cells by preventing normal glycosylation of the integrin beta1 chain of the collagen receptor. As a result, only the Ki-ras mutated cells exhibited altered cell to substratum attachment, whereas mutation of either Ras isoform activated mitogen-activated protein kinases. We have now asked whether intercellular adhesion proteins implicated in establishing basolateral polarity in colon epithelial cells are modulated by oncogenic Ki-Ras4BVal-12 proteins but not oncogenic Ha-RasVal-12 proteins. The embryonic adhesion protein carcinoembryonic antigen (CEA) was up-regulated on the mRNA and protein levels in each of three stable Ki-rasVal-12 transfectant lines but in none of three stable Ha-rasVal-12 transfectant lines. The elevated protein levels of CEA in Ki-ras4BVal-12 transfectant cells were decreased by blocking expression of Ki-ras4BVal-12 with antisense oligonucleotides. N-cadherin levels were decreased in only the Ki-ras transfectants, whereas E-cadherin levels were unchanged. Immunohistochemical analysis demonstrated that Ki-ras4BVal-12 transfectant cells did not polarize into cells with discrete apical and basal regions and so could not restrict expression of CEA to the apical region. These unpolarized cells displayed elevated levels of CEA all along their surface membrane where CEA mediated random, multilayered associations of tumor cells. This aggregation was both calcium-independent and blocked by Fab' fragments of anti-CEA monoclonal antibody col-1. Trafficking of the lysosomal cysteine protease cathepsin B may also be altered when cell polarity cannot be established. Ki-ras4BVal-12 transfectant cells expressed 2-fold elevated protein levels of the lysosomal cysteine protease cathepsin B but did not up-regulate cathepsin B mRNA expression. One function of oncogenic c-Ki-Ras proteins in colon cancer progression may be to up-regulate CEA and thus to prevent the lateral adhesion of adjacent colon epithelial cells that normally form a monolayer in vivo.
 ...
PMID:Oncogenic c-Ki-ras but not oncogenic c-Ha-ras up-regulates CEA expression and disrupts basolateral polarity in colon epithelial cells. 934 38

Metastatic rat colon cancer cells but not normal rat hepatocytes showed activity of cathepsin B on their plasma membranes. Activity was visualized in living cells with a new fluorogenic substrate, [Z-Arg]2-cresyl violet, and confocal microscopy. When these cancer cells were injected into the portal vein of rats, the animals developed tumors in the liver in a heterogeneous fashion. Three- to four-fold more tumors were found in the small caudate lobe than in the other three large lobes of the liver. Oral treatment with a selective water-soluble inhibitor of extracellular cathepsin B, Mu-Phe-homoPhe-fluoromethylketone, resulted in 60% reduction of the number of tumors and 80% reduction of the volume of tumors in the three large lobes whereas tumor development was not affected in the small caudate lobe. This study supports the conclusions that (a) extracellular cathepsin B plays a crucial but complex role in liver colonisation by rat colon carcinoma cells in vivo, (b) its selective inhibition suppresses tumor growth heterogeneously in the liver and (c) the caudate lobe of the liver is a relatively large risk factor for tumor development.
 ...
PMID:Heterogeneous suppression of experimentally induced colon cancer metastasis in rat liver lobes by inhibition of extracellular cathepsin B. 951 97

Signal amplification techniques greatly enhance the sensitivity of immunohistochemical (IHC) and in situ hybridization (ISH) methods. In particular, catalyzed signal amplification (CSA) using labeled tyramide or Nanogold-silver staining is an important signal amplification tool. We have applied a combination of both techniques, as has been introduced for ISH, for a further increase in sensitivity of an IHC method to detect cathepsin B. This lysosomal proteinase can also be expressed extracellularly, particularly in relation to cancer metastasis. Higher sensitivity of the IHC method was needed because existing methods failed to demonstrate cathepsin B protein where cathepsin B activity was found with a fluorescence enzyme histochemical method. Combined CSA and Nanogold-silver staining provided the sensitivity that was required. Moreover, this signal amplification method enabled the use of a 10-fold lower concentration of primary antibody (1 microg/ml). Nonspecific background staining was low provided that endogenous biotin, avidin, and peroxidase were completely blocked. The method was reproducible when all steps, and particularly the silver enhancement step, were rigidly controlled. The method resulted in localization patterns of cathepsin B protein that were in agreement with those of cathepsin B activity in serial sections of rat liver containing colon cancer metastases. We concluded that combined application of CSA and Nanogold-silver staining provides high sensitivity for immunohistochemical methods and that activity localization by an enzyme histochemical method is a very attractive alternative to IHC localization of an enzyme because it is at least as sensitive, it is rapid and simple, and it provides direct information on the function of an enzyme.
 ...
PMID:Signal amplification in immunohistochemistry at the light microscopic level using biotinylated tyramide and nanogold-silver staining. 1085 70

Some studies have shown the influence of proteases and vascular density in colorectal primary tumors on spreading and on the course of colorectal cancer. In the present study we have analyzed the relationships between overexpression of cathepsin B protein and angiogenesis intensity in resected colon tumors and their impact on prognosis. It has been investigated in a series of 90 colon cancer patients. Immunohistochemistry was used to evaluate cathepsin B overexpression in cancer cells and to visualize microvessels with antibodies against von Willebrand factor. Overexpression of cathepsin B was observed if more than 50% of cancer cells in searched field showed immunoreactivity with antibody against cathepsin B. Intensity of angiogenesis was evaluated as a mean number of microvessels from three fields with highest vessel number. In 36 cases (40%) overexpression of cathepsin B was detected. Increased angiogenesis (above median 31 vessels per 0.785 mm2) correlated positively with cathepsin B overexpression (p=0.0006). Higher vascular density associated with the presence of metastases in regional lymph nodes (p=0.01). Overexpression of cathepsin B was observed more often in group of older people (age above median 65 years; p=0.005). According to univariate analysis metastases in regional lymph nodes (p=0.0007), increased angiogenesis (p=0.0085), and distant metastases (p=0.02) were the features potentially influencing prognosis. Multivariate analysis revealed independent prognostic value only in case of metastases in regional lymph nodes (p=0.013) and when distant metastases were present (p=0.021), but not when increased angiogenesis in primary colon adenocarcinoma was observed (p=0.078). In conclusion we can say that there is a close relationship between intensity of angiogenesis and overexpression of cathepsin B protein in cancer cells in resected colon adenocarcinoma.
 ...
PMID:Overexpression of cathepsin B correlates with angiogenesis in colon adenocarcinoma. 1500 58

The p53 protein activates cellular death programs through multiple pathways. Because the high frequency of p53 mutations in human tumors is believed to contribute to resistance to commonly used chemotherapeutic agents, it is important to identify drugs that induce p53-independent cell death and to define the mechanisms of action of such drugs. Here we screened a drug library (the National Cancer Institute mechanistic set; 879 compounds with diverse mechanisms of actions) and identified 175 compounds that induced caspase cleavage of cytokeratin-18 in cultured HCT116 colon cancer cells at <5 microM. Interestingly, whereas most compounds elicited a stronger apoptotic response in cells with functional p53, significant apoptosis was observed also in p53-null cells. A subset of 15 compounds showing weak or no dependence on p53 for induction of apoptosis was examined in detail. Of these compounds, 11 were capable of activating caspase-3 in enucleated cells. Seven such compounds with nonnuclear targets were found to induce lysosomal membrane permeabilization (LMP). Translocation of the lysosomal proteases cathepsin B and cathepsin D into the cytosol was observed after treatment with these drugs, and apoptosis was inhibited by pepstatin A, an inhibitor of cathepsin D. Apoptosis depended on Bax, suggesting that LMP induced a mitochondrial apoptotic pathway. We conclude that a large number of potential anticancer drugs induce p53-independent apoptosis and that LMP is a mediator of many such responses.
 ...
PMID:Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis. 1561 92

Cathepsin B and pro-urokinase plasminogen activator (pro-uPA) localize to the caveolae of HCT 116 human colorectal carcinoma cells, an association mediated by active K-RAS. In this study, we established a stable HCT 116 cell line with a gene encoding antisense caveolin-1 (AS-cav-1) to examine the effects of caveolin-1, the main structural protein of caveolae, on the expression and localization of cathepsin B and pro-uPA, and their cell-surface receptors p11 and uPA receptor (uPAR), respectively. AS-cav-1 HCT 116 cells secreted less procathepsin B than control (empty vector) cells as measured by immunoblotting and pepsin activation of the proenzyme. Expression and secretion of pro-uPA was also downregulated in AS-cav-1 HCT 116 cells. Localization of cathepsin B and pro-uPA to caveolae was reduced in AS-cav-1 HCT 116 cells, and these cells expressed less total and caveolae-associated p11 and uPAR compared with control cells. Previous studies have shown that uPAR forms a complex with caveolin-1 and beta1-integrin, and we here show that downregulation of caveolin-1 also suppressed the localization of beta1-integrin to caveolae of these cells. Finally, downregulation of caveolin-1 in HCT 116 cells inhibited degradation of the extracellular matrix protein collagen IV and the invasion of these cells through Matrigel. Based on these results, we hypothesize that caveolin-1 affects the expression and localization of cathepsin B and pro-uPA, and their receptors, thereby mediating cell-surface proteolytic events associated with invasion of colon cancer cells.
 ...
PMID:Caveolin-1 mediates the expression and localization of cathepsin B, pro-urokinase plasminogen activator and their cell-surface receptors in human colorectal carcinoma cells. 1576 46

Tumor-derived proteins may occur in the circulation as a result of secretion, shedding from the cell surface, or cell turnover. We have applied an in-depth comprehensive proteomic strategy to plasma from intestinal tumor-bearing Apc mutant mice to identify proteins associated with tumor development. We used quantitative tandem mass spectrometry of fractionated mouse plasma to identify differentially expressed proteins in plasma from intestinal tumor-bearing Apc mutant mice relative to matched controls. Up-regulated proteins were assessed for the expression of corresponding genes in tumor tissue. A subset of proteins implicated in colorectal cancer were selected for further analysis at the tissue level using antibody microarrays, Western blotting, tumor immunohistochemistry, and novel fluorescent imaging. We identified 51 proteins that were elevated in plasma with concordant up-regulation at the RNA level in tumor tissue. The list included multiple proteins involved in colon cancer pathogenesis: cathepsin B and cathepsin D, cullin 1, Parkinson disease 7, muscle pyruvate kinase, and Ran. Of these, Parkinson disease 7, muscle pyruvate kinase, and Ran were also found to be up-regulated in human colon adenoma samples. We have identified proteins with direct relevance to colorectal carcinogenesis that are present both in plasma and in tumor tissue in intestinal tumor-bearing mice. Our results show that integrated analysis of the plasma proteome and tumor transcriptome of genetically engineered mouse models is a powerful approach for the identification of tumor-related plasma proteins.
 ...
PMID:Comprehensive proteome analysis of an Apc mouse model uncovers proteins associated with intestinal tumorigenesis. 1924 Feb 48


1 2 Next >>