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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We disclose a novel series of indenopyrazole-based cyclin-dependent kinase (CDK) inhibitors. Kinetic experiments confirmed our initial molecular modeling studies that the compounds are competitive with respect to adenosine 5'-triphosphate (ATP) and bind in the kinase ATP pocket. A unique combination of active pharmacophores led us to a series of semicarbazide-based inhibitors that are highly potent against CDK2 and CDK4 while maintaining selectivity against other relevant serine/threonine kinases. These compounds were active against a transformed human colon cancer cell line (HCT116) while maintaining an acceptable margin of activity against a normal fibroblast cell line. The compounds were found to be highly protein bound in our cell-based assay with the exception of 11k, which maintained a reasonable level of activity in the presence of human plasma proteins.
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PMID:Synthesis and evaluation of indenopyrazoles as cyclin-dependent kinase inhibitors. 2. Probing the indeno ring substituent pattern. 1243 Oct 50

Membrane type serine protease 1 (MT-SP1) is a representative member of a large family of related enzymes known as type II transmembrane serine proteases or membrane type serine proteases. MT-SP1 has been implicated in the selective proteolysis of key extracellular substrates but its physiological role is still not fully understood. MT-SP1 expression at the protein and RNA level has been previously examined by nonquantitative methods such as in situ hybridization, Northern blotting and immunohistochemistry. To establish an introductory understanding of the quantitative mRNA expression of MT-SP1 and to correlate these levels with urokinase-type plasminogen activator receptor (uPAR), a key component of extracellular proteolysis, quantitative RT-PCR was carried out. RNA expression was analyzed in 34 human cancer cell lines, 26 human tissues and 18 primary human breast cancer tissue samples. MT-SP1 mRNA is highly expressed in many breast, ovarian, prostate and colon cancer cell lines and normal human tissues of endodermal origin. At the transcript level, MT-SP1 shows a highly statistically significant correlation (Pearson's product moment correlation r = 0.784, p < 0.001) with uPAR in human breast cancer tissue. The exact role of MT-SP1 in concert with proteins such as uPAR and other members of the plasminogen activator cascade has yet to be ascertained. However, the significant correlation between MT-SP1 and uPAR transcript levels in this initial study suggests further work to establish the role of MT-SP1 as a possible prognostic, diagnostic or therapeutic target for breast cancer.
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PMID:Quantitation of membrane type serine protease 1 (MT-SP1) in transformed and normal cells. 1267 19

The traditional view on the role of serine proteases in tumor biology has changed with the recent discovery of a family of protease-activated receptors (PARs). In this study we explored the expression and functional role of the thrombin receptor PAR-1 in human colon cancer cells. Reverse transcriptase-polymerase chain reaction analysis showed that PAR-1 mRNAs are present in 11 of 14 human colon cancer cell lines tested but not in normal human colonic epithelial cells. This is in line with the immunolocalization of PAR-1 in human colon tumors and its absence in normal human colonic mucosa. The functional significance of the aberrant expression of PAR-1 in colon cancer cells was then investigated. We found that 1) a prompt increase in intracellular calcium concentration was observed on thrombin (10 nmol/L) or PAR-1 agonist AP1 (100 micro mol/L) challenge of HT29 cells; 2) HT29 quiescent cells treated with thrombin (0.01 to 20 nmol/L) or AP1 (1 to 300 micro mol/L) exhibited dramatic mitogenic responses (3.5-fold increase in cell number). Proliferative effects of thrombin or AP1 were also observed in other colon cancer cell lines expressing PAR-1. This effect was reversed by the MEK inhibitor PD98059 in consonance with the ability of thrombin or AP1 to induce phosphorylation of p42/p44 extracellular-regulated protein kinases. 3) PAR-1 activation by thrombin or AP1 led to a two-fold increase in cell motility of wounded HT29-D4. Our results demonstrate for the first time the aberrant expression of the functional thrombin receptor PAR-1 in colon cancers and its important involvement in cell proliferation and motility. Thrombin should now be considered as a growth factor for human colon cancer.
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PMID:Aberrant expression and activation of the thrombin receptor protease-activated receptor-1 induces cell proliferation and motility in human colon cancer cells. 1270 33

In colon cancer, enteric bacteria and dietary factors are major determinants of the microenvironment but their effect on cellular invasion is not known. We therefore incubated human HCT-8/E11 colon cancer cells with bacteria or bacterial conditioned medium on top of collagen type I gels. Listeria monocytogenes stimulate cellular invasion through the formation of a soluble motility-promoting factor, identified as a 13mer beta-casein-derived peptide (HKEMPFPKYPVEP). The peptide is formed through the combined action of Mpl, a Listeria thermolysin-like metalloprotease, and a collagen-associated trypsin-like serine protease. The 13mer peptide was also formed by tumour biopsies isolated from colon cancer patients and incubated with a beta-casein source. The pro- invasive 13mer peptide-signalling pathway implicates activation of Cdc42 and inactivation of RhoA, linked to each other through the serine/threonine p21- activated kinase 1. Since both changes are necessary but not sufficient, another pathway might branch upstream of Cdc42 at phosphatidylinositol 3-kinase. Delta opioid receptor (deltaOR) is a candidate receptor for the 13mer peptide since naloxone, an deltaOR antagonist, blocks both deltaOR serine phosphorylation and 13mer peptide-mediated invasion.
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PMID:Beta-casein-derived peptides, produced by bacteria, stimulate cancer cell invasion and motility. 1460 61

Mucins are high-molecular weight epithelial glycoproteins with a high content of clustered oligosaccharides O-glycosidically linked to tandem repeat peptides rich in threonine, serine, and proline. There are two structurally and functionally distinct classes of mucins: secreted gel-forming mucins (MUC2, MUC5AC, MUC5B, and MUC6) and transmembrane mucins (MUC1, MUC3A, MUC3B, MUC4, MUC12, MUC17), although the products of some MUC genes do not fit well into either class (MUC7, MUC8, MUC9, MUC13, MUC15, MUC16). MUC1 mucin, as detected immunologically, is increased in expression in colon cancers, which correlates with a worse prognosis. Expression of MUC2 secreted gel-forming mucin is generally decreased in colorectal adenocarcinoma, but preserved in mucinous carcinomas, a distinct subtype of colon cancer associated with microsatellite instability. Another secreted gel-forming mucin, MUC5AC, a product of normal gastric mucosa, is absent from normal colon, but frequently present in colorectal adenomas and colon cancers. The O-glycosidically linked oligosaccharides of mucins can be described in terms of core type, backbone type, and peripheral structures. Colon cancer mucins have differences in both core carbohydrates and in peripheral carbohydrate structures that are being investigated as diagnostic and prognostic markers, and also as targets for cancer vaccines. Colon cancer mucins typically have increases in three core structures: Tn antigen (GalNAcalphaThr/Ser), TF antigen (Galbeta3GalNAc) and sialyl Tn (NeuAcalpha6GalNAc). The type 3 core (GlcNAcbeta3Ga1NAc) predominant in normal colonic mucin is lacking in colon cancer mucins. There are cancer-associated alterations in the peripheral carbohydrates of colonic mucins including a decrease in O-acetyl-sialic acid and a decrease in sulfation. There are, however, cancer-associated increases in sialyl LeX and related structures on mucins and other glycoproteins that can serve as ligands for selectins, increasing the metastatic capacity of colon cancer cells. The endogenous galactoside-binding protein galectin-3, which is expressed at higher levels in colon cancers than normal colon, binds to colon cancer mucin as well as other glycoproteins. Interference of the binding of selectins and galectin-3 to mucin may show therapeutic or preventative promise for colon cancer.
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PMID:Mucins and mucin binding proteins in colorectal cancer. 1500 Jan 51

Cancer cells are thought to possess mechanisms for evading the host's immune surveillance system. Survivin, a member of the inhibitor-of-apoptosis family overexpressed by cancer cells, inhibits Fas-mediated apoptosis induced by immune cells. In addition, cancer cells express Fas ligand (FasL) on their surfaces as a counterattack against immune cells. Mechanisms by which cancer cells express FasL, including involvement of survivin, are unclear. In the present study, we demonstrated that survivin up-regulated FasL expression and investigated how this might occur. Quantitative immunostaining showed correlation between survivin and FasL protein expression in colon cancer tissues (r=0.79). FasL expression was up-regulated in LS180 colon cancer cells transfected with the survivin gene. Transfectants showed increased cytotoxicity against a Fas-sensitive human T leukemia cell line, Jurkat. In contrast, FasL expression was down-regulated in SW480 cells transfected with a small inhibitory RNA to prevent survivin expression. Survivin gene transfectants showed increased DNA binding of transcription factor specificity protein 1 (Sp1) to the FasL promoter, and up-regulation of Sp1 phosphorylation at serine and threonine residues; the total amount of Sp1 was unchanged. Thus, survivin enables cancer cells not only to suppress immune cell attack by inhibiting Fas-mediated apoptotic signaling, but to attack immune cells by induction of FasL.
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PMID:Survivin enhances Fas ligand expression via up-regulation of specificity protein 1-mediated gene transcription in colon cancer cells. 1500

The specific mechanisms controlling the transition from proliferation to terminal differentiation in human intestinal epithelial cells (HIEC) remain largely undefined. Herein, we analyzed the expression and localization of Rb and E2F proteins in well-established normal intestinal epithelial cell models which allow for the re-enactment of the crypt-villus axis in vitro as well as in intact epithelium and in colon cancer cells. We report that (1) expression of E2F1 is down-regulated while E2F4 protein is sequestered in the cytoplasm during G(0) arrest associated with serum deprivation, confluency, and terminal differentiation of intestinal cells; (2) concurrently, there is an accumulation of the hypophosphorylated form of the pocket proteins into the nucleus with an increased association of E2F4 with pRb and p130; (3) cells which expressed high levels of nuclear E2F4 are all positive for Ki67 staining in human fetal intestine; (4) activation of HIEC crypt cells by growth factors leads to an increase in the nuclear localization of E2F4 which may be attributable to a decrease in the serine/threonine phosphorylation of this transcription factor; (5) inhibition of p38 MAP kinase with alpha/beta inhibitor SB203580 induces E2F4 translocation into the nucleus and its transcriptional activity. In conclusion, our data suggest a key role for E2F4 in proliferation of human intestinal crypt cells and that its cytoplasmic retention as well as its sequestration by Rb proteins may represent a critical step in initiating cell-cycle exit.
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PMID:The nucleocytoplasmic shuttling of E2F4 is involved in the regulation of human intestinal epithelial cell proliferation and differentiation. 1504 9

AIE-75 has been known as a 75-kDa autoantigen detected in the serum of autoimmune enteropathy (AIE) and as a colon cancer-related antigen, and now designated as a gene causative of Usher syndrome type 1C hereditary syndromic hearing loss. It binds to a novel putative tumor suppressor MCC2 that is homologous to MCC (mutated in colon cancer) through a PSD-95/Dlg/ZO-1 (PDZ) domain. To clarify the functional role in colon cancer cells, we transfected AIE-75 gene into SW480 colon cancer cells which do not express AIE-75. Expression of AIE-75 suppressed growth of SW480 cells in vitro in correlation with the expression levels. It was due mainly to G2/M phase cell cycle arrest associated with mitotic slippage, resulting in emergence of hyperploid giant-nucleated or multi-nucleated cells. Screening of proteins that bound to PDZ domains of AIE-75 by a yeast two hybrid system showed that three serine/threonine phosphatase catalytic subunits (PP2AC-alpha, PP2AC-beta, and PPP6C) could bind to AIE-75. Since PP2AC is known to regulate G2/M checkpoint, we suggest that AIE-75 interacts with PP2AC and prevent cells to transit mitotic phase.
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PMID:Expression of AIE-75 PDZ-domain protein induces G2/M cell cycle arrest in human colorectal adenocarcinoma SW480 cells. 1521 44

Gabexate mesilate (GM), a synthetic protease inhibitor, has an antiproteinase activity on various types of plasma serine proteases. However, its role on matrix metalloproteinases (MMPs) has not been identified. In this study, we investigated the effect of GM on MMPs and on the invasion and metastasis of human colon cancer cell lines and neoangiogenesis. The activities of MMPs secreted from these cells were significantly reduced by GM but unaffected by the serine protease inhibitor aprotinin. GM directly inhibited purified progelatinase A derived from T98G human glioblastoma cells. In vitro, GM significantly reduced the invasive ability of colon cancer cells but not cellular motility, whereas aprotinin affected neither. Liver metastatic ability and tumorigenic potential in nude mice were remarkably reduced on treatment with GM. Immunohistochemical analysis of GM-treated tumors in mice showed a marked increase in apoptosis and a significant reduction in tumor angiogenesis. Human umbilical vein endothelial cell proliferation, tube formation, and neoangiogenesis in the rabbit cornea and Matrigel implanted in mice were significantly inhibited by GM. These results suggest that GM is a novel inhibitor of MMPs and that it may inhibit the invasion and metastasis of human colon cancer cells by blocking MMPs and neoangiogenesis.
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PMID:Gabexate mesilate inhibits colon cancer growth, invasion, and metastasis by reducing matrix metalloproteinases and angiogenesis. 1524 May 44

Protein phosphatase 2A (PP2A) is a family of mammalian serine/threonine phosphatases that is involved in the control of many cellular functions including those mediated by extracellular signal-regulated kinase (ERK) signaling. While investigating the reversible antiproliferative effect of the dietary lectin, jacalin, which binds the Thomsen-Friedenreich antigen (galactose beta1-3 N-acetylgalactosamine alpha-), we have found that this lectin (30 microg/ml) induces rapid, transient, tyrosine phosphorylation of putative human HLA-DR-associated protein I (PHAPI, also known as the tumor suppressor pp32) in HT29 human colon cancer cells. This is accompanied by the release of PP2A from association with PHAPI, allowing increased phosphatase activity of PP2A (by 42 +/- 10% at 10 min) and consequent complete dephosphorylation of the ERK kinase, MEK1/2, by 10 min and of ERK1/2 by 60 min. PHAPI knockdown by RNA interference abolished the effects of jacalin on PP2A activation and MEK inhibition. Thus phosphorylation of PHAPI/pp32 is a critical regulatory step in PP2A activation and ERK signaling.
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PMID:Protein phosphatase 2A, a negative regulator of the ERK signaling pathway, is activated by tyrosine phosphorylation of putative HLA class II-associated protein I (PHAPI)/pp32 in response to the antiproliferative lectin, jacalin. 1524 76


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