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

The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses with no signs of toxicity, and correlated with a reduction in the levels of activated mitogen-activated protein kinase in excised tumors. These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.
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PMID:Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. 1039 14

We have cloned a novel gene mirk (minibrain-related kinase) encoding a protein kinase that enables colon carcinoma cells to survive under certain stress conditions. Mirk is a mitogen-activated protein kinase substrate but is down-regulated by activated extracellular signal-regulated kinases (erks) in vivo. Mirk contains a PEST region characteristic of rapidly turned over proteins and is broken down to a Mr 57,000 form only in the nucleus. In each of three colon carcinoma cell lines, mirk levels were increased 20-fold when erk activation was blocked by the MEK inhibitor PD98059 in serum-free medium. Addition of IGF-I to activate erks blocked this increase. Mirk was stably overexpressed in two colon carcinoma cell lines to attain levels seen in colon cancers. Each of five mirk transfectants proliferated when switched to serum-free medium and regained rapid growth when serum was restored, whereas five vector control transfectants and three kinase-dead mutant mirk transfectants did not. mirk mRNA levels were elevated in several types of carcinomas, and mirk protein was detected in each of seven colon carcinoma cell lines. mirk was expressed at a higher protein level in Western blots from three of eight colon cancers compared with paired normal colon tissue, suggesting that mirk plays a role in the evolution of a subset of colon cancers. mirk is not mutated in colon carcinomas. Mirk may mediate tumor cell survival in mitogen-poor environments or early in colon cancer development before many autocrine growth factors have been induced.
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PMID:Mirk protein kinase is a mitogen-activated protein kinase substrate that mediates survival of colon cancer cells. 1091 78

Three distinct groups of mitogen-activated protein kinases (MAPKs) have been identified in mammalian cells (i.e., ERK, JNK, and p38) which play an important role in the differentiation and apoptosis of various cells. The purpose of our present study was to determine MAPK activity and levels associated with sodium butyrate (NaBT)-mediated differentiation and apoptosis in the human colon cancer cell lines Caco-2 and HT29. Intestinal alkaline phosphatase (IAP) activity, a marker of intestinal differentiation, was increased at 48 h after NaBT treatment followed by cell death at 72 h. ERK activity was decreased in differentiated Caco-2 cells either induced with NaBT or allowed to differentiate spontaneously and in HT29 cells treated with NaBT. The combination of the MEK inhibitor, PD98059, with NaBT further increased IAP activity and cell death compared with NaBT alone. In contrast to ERK, JNK1 activity and c-Jun phosphorylation was increased 8 h after NaBT treatment suggesting a role for the JNK pathway in intestinal cell differentiation and apoptosis. p38 activity was increased at 24 and 48 h after NaBT treatment. Taken together, our results suggest that alterations in MAPKs (i.e., ERK inhibition and JNK induction) contribute to the differentiation and apoptotic pathways in intestinal cells.
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PMID:Alterations of MAPK activities associated with intestinal cell differentiation. 1139 74

Integrins play an important role in tumour progression by influencing cellular responses and matrix-dependent adhesion. However, the regulation of matrix-dependent adhesion assembly in epithelial cells is poorly understood. We have investigated the integrin and signalling requirements of cell-matrix adhesion assembly in colon carcinoma cells after plating on fibronectin. Adhesion assembly in these, and in the adenoma cells from which they were derived, was largely dependent on alpha v beta 6 integrin and required phosphorylation of FAK on tyrosine-397. The rate of fibronectin-induced adhesion assembly and the expression of both alpha v beta 6 integrin and FAK were increased during the adenoma-to-carcinoma transition. The matrix-dependent adhesion assembly process, particularly the final stages of complex protrusion that is required for optimal cell spreading, required the activity of extracellular signal-regulated kinase (ERK). Furthermore, phosphorylated ERK was targeted to newly forming cell--matrix adhesions in the carcinoma cells but not the adenoma cells, and inhibition of FAK--tyrosine-397 phosphorylation or MEK suppressed the appearance of phosphorylated ERK at peripheral sites. In addition, inhibition of MEK--ERK activation blocked the formation of peripheral actin microspikes that were necessary for the protrusive phase of cell-matrix adhesion assembly. Thus, MEK--ERK--dependent peripheral actin re-organization is required for the full development of integrin-induced adhesions and this pathway is stimulated in an in vitro model of colon cancer progression.
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PMID:The protrusive phase and full development of integrin-dependent adhesions in colon epithelial cells require FAK- and ERK-mediated actin spike formation: deregulation in cancer cells. 1149 15

Matrix metalloproteinase-9 (MMP-9) plays important roles in tumor invasion and angiogenesis. Secretion of MMP-9 has been reported in various cancer types including lung cancer, colon cancer, and breast cancer. In our investigation of MMP-9 regulation by growth factors, MMP-9 was activated by heregulin-beta1 as shown by zymography in both SKBr3 and MCF-7 breast cancer cell lines. Increase in MMP-9 activity was due to increased MMP-9 protein and mRNA levels, which mainly results from transcriptional upregulation of MMP-9 by heregulin-beta1. Heregulin-beta1 activates multiple signaling pathways in breast cancer cells, including Erk, p38 kinase, PKC, and PI3-K pathways. We examined the pathways involved in heregulin-beta1-mediated MMP-9 activation using chemical inhibitors that specifically inhibit each of these heregulin-beta1-activated pathways. The PKC inhibitor RO318220 and p38 kinase inhibitor SB203580 completely blocked heregulin-beta1-mediated activation of MMP-9. MEK-1 inhibitor PD098059 partially blocked MMP-9 activation, whereas PI3-K inhibitor wortmannin had no effect on heregulin-beta1-mediated MMP-9 activation. Therefore, at least three signaling pathways are involved in the activation of MMP-9 by heregulin-beta1. Since MMP-9 is tightly associated with invasion/metastasis and angiogenesis, our studies suggest that blocking heregulin-beta1-mediated activation of MMP-9 by inhibiting the related signaling pathways may provide new strategies for inhibition of cancer metastasis and angiogenesis.
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PMID:Multiple signaling pathways involved in activation of matrix metalloproteinase-9 (MMP-9) by heregulin-beta1 in human breast cancer cells. 1178 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

Gastrin has the ability to stimulate cell growth in some colorectal cancer cells and some of these cells also express gastrin/CCKB receptors, suggesting that gastrin and its autocrine loop are involved in their proliferation. We previously reported that oncogenic ras induced gastrin gene expression in colon cancer cells. The aim of this study was to investigate whether oncogenic ras also induces gastrin/CCKB receptor gene expression. A transiently transfected activated ras vector stimulated gastrin/CCKB receptor transcriptional activities in both Colo320HSR and LoVo cells, but these ras-increased activities were inhibited by a specific MEK inhibitor, PD98059. An RPA demonstrated that activated ras increased endogenous gastrin/CCKB receptor mRNA levels and PD98059 decreased them in LoVo cells. These findings suggest that oncogenic ras induces gastrin/CCKB receptor gene expression through some intracellular signaling pathways, including MEK, in colon cancer cell lines.
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PMID:Oncogenic ras induces gastrin/CCKB receptor gene expression in human colon cancer cell lines LoVo and Colo320HSR. 1276 77

Since ethacrynic acid (EA), an SH modifier as well as glutathione S-transferase (GST) inhibitor, has been suggested to induce apoptosis in some cell lines, its effects on a human colon cancer cell line DLD-1 were examined. EA enhanced cell proliferation at 20-40 microM, while it caused cell death at 60-100 microM. Caspase inhibitors did not block cell death and DNA ladder formation was not detected. Poly(ADP-ribose) polymerase, however, was cleaved into an 82-kDa fragment, different from an 85-kDa fragment that is specific for apoptosisis. The 82-kDa fragment was not recognized by antibody against PARP fragment cleaved by caspase 3. N-Acetyl-L-cysteine (NAC) completely inhibited EA-induced cell death, but 3(2)-t-butyl-4-hydroxyanisole or pyrrolidinedithiocarbamate ammonium salt did not. Glutathione (GSH) levels were dose-dependently increased in cells treated with EA and this increase was hardly affected by NAC addition. Mitogen-activated protein kinase (MAPK) kinase (MEK) 1, extracellular signal-regulated kinase (ERK) 1 and GST P1-1 were increased in cells treated with 25-75 microM EA, while c-Jun N-terminal kinase (JNK) 1 and p38 MAPK were markedly decreased by 100 microM EA. NAC repressed EA-induced alterations in these MAPKs and GST P1-1. p38 MAPK inhibitors, SB203580 and FR167653, dose-dependently enhanced EA-induced cell death. An MEK inhibitor, U0126, did not affect EA-induced cell death. These studies revealed that EA induced cell death concomitantly with a novel PARP fragmentation, but without DNA fragmentation. p38 MAPK was suggested to play an inhibitory role in EA-induced cell death.
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PMID:Characterization of cell death induced by ethacrynic acid in a human colon cancer cell line DLD-1 and suppression by N-acetyl-L-cysteine. 1455 62

The AP-1 (activator protein-1) complex, which consists of proteins of the Fos and Jun families, is thought to play an important role in the balance between cell proliferation and apoptosis, the response to genotoxic stress and cell transformation. In cells containing oncogenic Ras, the major components of AP-1 are Fra-1 and c-Jun. Signalling from Ras to AP-1 is through the Raf/MEK[mitogen-activated protein (MAP) kinase kinase]/ERK (extracellular signal-regulated kinase) MAP kinase pathway as sustained activation of Raf1 or Mek1 modifies AP-1 composition and activity. To analyse the potential link between the ERK-MAPK pathway and AP-1 in colon cancer, in which RAS and BRAF mutations are frequent, we have studied the regulation of AP-1 in colon carcinoma cell lines. We show that c-JUN and FRA-1 expression is dependent on ERK activity and that different thresholds of ERK activity control the expression of FRA-1. A basal activity is required to induce transcription of the FRA-1 gene, but additional higher levels of activity stabilize FRA-1 against proteasome-dependent degradation. These results provide a clear-cut example that the magnitude of ERK signalling affects the cellular response. Although we find no contribution of FRA-1 towards cell proliferation of adherent tumour cells, the high levels of FRA-1 in cells where elevated ERK activity leads to protein stabilization provide survival signals for tumour cells removed from the extracellular matrix.
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PMID:Elevated ERK-MAP kinase activity protects the FOS family member FRA-1 against proteasomal degradation in colon carcinoma cells. 1462 89

Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are cytoplasmic adapter proteins that link a wide variety of cell surface receptors to the apoptotic signaling cascade. The purpose of this study was to delineate the signaling pathways and TRAF1 promoter elements responsible for phorbol ester-mediated TRAF1 induction in human colon cancers. Here, we found that the PKC activators, phorbol 12-myristate 13-acetate (PMA) and bryostatin I, induced TRAF1 mRNA expression; pretreatment with actinomycin D blocked PMA-mediated TRAF1 expression suggesting induction at the transcriptional level. In contrast, expression of other TRAFs (TRAF2, 3 and 4) was minimally altered by PMA. Various PKC isoform-selective inhibitors blocked PMA-mediated TRAF1 mRNA and promoter stimulation; rottlerin, a selective PKCdelta inhibitor, had no effect suggesting that Ca(2+)-dependent PKC isoforms (e.g., PKCalpha and betaI) play a role in TRAF1 regulation. In addition, the MEK/ERK inhibitors, PD98059 and UO126, suppressed PMA-stimulated TRAF1 promoter activity indicating a role for ERK in TRAF1 induction. Moreover, cotransfection of a dominant-negative Raf-1 (Raf-C4) significantly reduced PMA-stimulated TRAF1 promoter activity whereas transfection of dominant-negative Ras or treatment with Ras inhibitors had minimal to no effect on TRAF1 induction suggesting dependence on Raf, but not Ras, activation. Finally, site-specific mutagenesis of functional NF-kappaB sites (particularly the most proximal site) in the TRAF1 promoter significantly decreased PMA-mediated promoter activity. In conclusion, our results demonstrate selective induction of TRAF1 in human colon cancer cells through a Ca(2+)-dependent PKC/Raf-1/ERK/NF-kappaB-dependent pathway.
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PMID:Regulation of phorbol ester-mediated TRAF1 induction in human colon cancer cells through a PKC/RAF/ERK/NF-kappaB-dependent pathway. 1498 39


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