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

Over the last decade, the critical role of the proteasome in cell-cycle regulation has become increasingly apparent. The proteasome, a multicatalytic protease present in all eukaryotic cells, is the primary component of the protein degradation pathway of the cell. By degrading regulatory proteins (or their inhibitors), the proteasome serves as a central conduit for many cellular regulatory signals and, thus, is a novel target for therapeutic drugs. PS-341 is a small molecule that is a potent and selective inhibitor of the proteasome. In vitro and mouse xenograft studies of PS-341 have shown antitumor activity in a variety of tumor types, including myeloma, chronic lymphocytic leukemia, prostate cancer, pancreatic cancer, and colon cancer, among others. Although PS-341 rapidly leaves the vascular compartment, a novel pharmacodynamic assay has shown that inhibition of proteasome-the biologic target-is dose dependent and reversible. These studies provided the rationale for a twice-weekly dosing schedule employed in ongoing clinical studies. Phase I trials in a variety of tumor types have shown PS-341 to be well tolerated, and phase II trials in several hematologic malignancies and solid tumor types are now in progress. Efficacy and safety data from the most advanced of these, a phase II multicenter trial in myeloma, will be available in early 2002.
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PMID:Development of the proteasome inhibitor PS-341. 1185 43

A novel phosphorylation-specific antibody (alphapbeta-catenin) was generated against a peptide corresponding to amino acids 33-45 of human beta-catenin, which contained phosphorylated serines at positions 33 and 37. This antibody is specific to phosphorylated beta-catenin and reacts neither with the non-phosphorylated protein nor with phosphorylated or non-phosphorylated plakoglobin. It weakly interacts with S33Y beta-catenin but not with the S37A mutant. pbeta-catenin is hardly detectable in normal cultured cells and accumulates (up to 55% of total beta-catenin) upon overexpression of the protein or after blocking its degradation by the proteasome. Inhibition of both GSK-3beta and the proteasome resulted in a rapid (t1/2=10 minutes) and reversible reduction in pbeta-catenin levels, suggesting that the protein can undergo dephosphorylation in live cells, at a rate comparable to its phosphorylation by GSK-3beta. pbeta-catenin interacts with LEF-1, but fails to form a ternary complex with DNA, suggesting that it is transcriptionally inactive. Immunofluorescence microscopy indicated that pbeta-catenin accumulates in the nuclei of MDCK and BCAP cells when overexpressed and is transiently associated with adherens junctions shortly after their formation. pbeta-catenin only weakly interacts with co-transfected N-cadherin, although it forms a complex with the ubiquitin ligase component beta-TrCP. SW480 colon cancer cells that express a truncated APC, at position 1338, contain high levels of pbeta-catenin, whereas HT29 cells, expressing APC truncated at position 1555, accumulate non-phosphorylated beta-catenin, suggesting that the 1338-1555 amino acid region of APC is involved in the differential regulation of the dephosphorylation and degradation of pbeta-catenin.
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PMID:Regulation of S33/S37 phosphorylated beta-catenin in normal and transformed cells. 1207 67

The proteasome is a multicatalytic protease, present in all eukaryotic cells, that is primarily responsible for intracellular protein degradation. By destroying regulatory proteins or their inhibitors, the proteasome influences many cellular regulatory signals and is thus a potential target for pharmacological agents. The dipeptide boronic acid analogue PS-341 is a potent and selective proteasome inhibitor in clinical trials for a variety of tumor types. In vitro and in vivo (murine xenograft) studies show that PS-341 has activity against a variety of malignancies, including myeloma, chronic lymphocytic leukemia, prostate cancer, pancreatic cancer, breast cancer and colon cancer.
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PMID:Preclinical and clinical evaluation of proteasome inhibitor PS-341 for the treatment of cancer. 1213 26

Upregulation of nuclear factor (NF)-kappaB is found in many forms of cancer. Activation of NF-kappaB in cancer cells by chemotherapy or radiation can blunt the ability of this therapy to induce cell death. Proteasome inhibitors stimulate apoptosis in part via prevention of NF-kappaB activation. We sought to determine whether constitutive NF-kappaB activity is present in human colon cancer. In addition we studied whether alterations of NF-kappaB activity with a proteasome inhibitor would prevent colon cancer cell growth and induce apoptosis. We demonstrated constitutive transcriptional activation of NF-kappaB in SW48 and SW116 colon cancer cells by luciferase and electromobility shift assays. This was confirmed by p65 immunostaining. This activity was further induced in the presence of chemotherapy. In colon cancer specimens constitutive activation of NF-kappaB was observed in the majority of tumors. Treatment with the proteasome inhibitor (MG-132) inhibited growth and also stimulated apoptosis of colon cancer cells. We conclude that inhibition of NF-kappaB activation may be a logical therapy for certain cancers. This can be done via specific approaches on molecules necessary for keeping NF-kappaB inactivated in the cytoplasm. Other potentially useful ways to promote apoptosis in cancer cells include the utilization of proteasome inhibitors. Such inhibitors are currently being evaluated in clinical trials.
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PMID:Antineoplastic therapy in colorectal cancer through proteasome inhibition. 1257 74

Activated Wnt signaling pathways have been found in various human cancers, including those of the colon, liver, endometrium, ovary, prostate, and stomach. As a result, beta-catenin is accumulated and becomes transcriptionally active for proliferative genes and oncogenes. Wnt pathway mutations result in biochemical mechanisms yielding inefficient phosphorylation of beta-catenin by GSK3beta due to APC, beta-catenin and/or axin mutations. Therefore, the needs and the opportunity to develop new cancer therapies exist through reversing oncogenic APC/beta-catenin/Lef/Tcf signals. Exisulind and analogues are inhibitors of cyclic GMP phosphodiesterases (PDE) that have been shown to activate and induce protein kinase G. The data show PKG regulation of beta-catenin in wnt signaling, accounting, at least in part, for apoptosis induction in treated colon cancer cells carrying either APC or beta-catenin mutations. Exisulind and analogs reduce beta-catenin via a novel, GSK3beta independent processing mechanism. Activated PKG directly phosphorylate beta-catenin at its C-terminal domain and causes proteasome dependent degradation of the protein. Since this pathway is independent of APC and GSK3beta, exisulind and analogs provide a superior approach to circumvent the molecular defects of wnt signaling pathway and to treat cancers with such defects.
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PMID:beta-Catenin signaling: therapeutic strategies in oncology. 1264 83

We demonstrate that PS-341, a small molecule inhibitor of the proteasome, markedly sensitizes resistant prostate, colon, and bladder cancer cells to TNF-like apoptosis-inducing ligand (TRAIL)-induced apoptosis irrespective of Bcl-xL overexpression. PS-341 treatment by itself does not affect the levels of Bax, Bak, caspases 3 and 8, c-Flip or FADD, but elevates levels of TRAIL receptors DR4 and DR5. This increase in receptor protein levels is associated with the ubiquitination of the DR5 protein. When PS-341 is combined with TRAIL, the levels of activated caspase 8 and cleaved Bid are substantially increased. In Bax-negative TRAIL-resistant HC-4 colon cancer cells, the combination of PS-341 and TRAIL overcomes the block to activation of the mitochondrial pathway and causes SMAC and cytochrome c release followed by apoptosis. Similarly, murine embryonic fibroblasts lacking Bax undergo apoptosis when exposed to the combination of PS-341 and TRAIL; however, fibroblasts lacking Bak are significantly resistant. Taken together, these findings indicate that PS-341 enhances TRAIL-induced apoptosis by increasing the cleavage of caspase 8, causing Bak-dependent release of mitochondrial proapoptotic proteins.
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PMID:The proteasome inhibitor PS-341 overcomes TRAIL resistance in Bax and caspase 9-negative or Bcl-xL overexpressing cells. 1290 78

Colorectal cancer (CRC) is the second leading cause of cancer death in the USA. Accumulation of beta-catenin protein is nearly ubiquitous in colon adenomas and cancers, presumably due to mutations in the APC or beta-catenin genes that inhibit proteasome-dependent degradation of beta-catenin protein. Substantial clinical, epidemiological, and animal evidence indicate that sulindac and other non-steroidal anti-inflammatory drugs (NSAIDs) prevent the development of CRC. The mechanisms by which sulindac exerts its potent growth inhibitory effects against colon tumor cells are incompletely understood, but down-regulation of beta-catenin has been suggested as one potential mechanism. The goal of this study was to determine the mechanism of beta-catenin protein down-regulation by sulindac metabolites. Treatment of human colon cancer cell lines with apoptotic concentrations of sulindac metabolites (sulindac sulfide, sulindac sulfone) induced a dose- and time-dependent inhibition of beta-catenin protein expression. Inhibition of proteasome activity with MG-132 partially blocked the ability of sulindac sulfide and sulindac sulfone to inhibit beta-catenin protein expression. Pretreatment with the caspase inhibitor z-VAD-fmk blocked morphological signs of apoptosis as well as caspase cleavage, and also partially prevented beta-catenin degradation by sulindac metabolites. These effects occurred in cells with bi-allelic APC mutation (SW480), with wild-type APC but mono-allelic beta-catenin mutation (HCT116) and in cells that lack expression of either COX-1 or -2 (HCT15). These results indicate that loss of beta-catenin protein induced by sulindac metabolites is COX independent and at least partially due to reactivation of beta-catenin proteasome degradation and partially a result of caspase activation during the process of apoptosis.
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PMID:Sulindac metabolites induce caspase- and proteasome-dependent degradation of beta-catenin protein in human colon cancer cells. 1455 7

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

Targeting the ubiquitin-proteasome pathway has emerged as a promising approach for treating cancer. Bortezomib (VELCADE, formerly known as PS-341), a potent and reversible proteasome inhibitor, is being evaluated in clinical trials for treating multiple myeloma, and various other types of hematologic and solid tumors. Proteasome inhibitors are known to induce apoptosis in human cancer cells. Nevertheless, the mechanisms of apoptosis induced by proteasome inhibitors remain unclear. In this study, we investigated the role of p53 and its downstream targets in bortezomib-induced apoptosis in HCT116 human colon cancer cells. We demonstrated that bortezomib induced p53, and activated its downstream genes p21, PUMA and Bax in a p53-dependent fashion. However, apoptotic response to bortezomib was not affected by the deletion of p53. Surprisingly, we found that bortezomib-induced apoptosis was markedly enhanced in the p21-knockout cells, while significantly decreased in the BAX-knockout cells. Furthermore, in the cells deficient for both Bax and p21, apoptosis was restored to the level in the parental or the p53-deficient cells. The opposite effects of Bax and p21 were unrelated to the extent of proteasome inhibition, and were also observed in cells treated with different proteasome inhibitors. These results indicate that p53 downstream targets can collectively modulate apoptotic response to bortezomib and other proteasome inhibitors.
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PMID:Differential apoptotic response to the proteasome inhibitor Bortezomib [VELCADE, PS-341] in Bax-deficient and p21-deficient colon cancer cells. 1468 80

The dipeptide boronic acid analogue VELCADE (Bortezomib; formerly known as PS-341, LDP-341 and MLM341) is a potent and selective inhibitor of the proteasome, a multicatalytic enzyme that mediates many cellular regulatory signals by degrading regulatory proteins or their inhibitors. The proteasome is, thus, a potential target for pharmacological agents. Bortezomib, the first proteasome inhibitor to reach clinical trials, has shown in vitro and in vivo activity against a variety of malignancies, including myeloma, chronic lymphocytic leukemia, prostate cancer, pancreatic cancer, and colon cancer. The drug is rapidly cleared from the vascular compartment, but a novel pharmacodynamic assay has shown that bortezomib--mediated proteasome blockade is dose-dependent and reversible. Based on phase I studies demonstrating that bortezomib has manageable toxicities in patients with advanced cancers, phase II trials have been initiated for both solid and hematological malignancies.
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PMID:Development of the proteasome inhibitor Velcade (Bortezomib). 1519 12


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