Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Epidemiological and preclinical studies demonstrate that consumption of diets high in omega-3 polyunsaturated fatty acids reduces the risk of colon cancer. Inhibition of colon carcinogenesis by omega-3 polyunsaturated fatty acids is mediated through modulation of more than one signaling pathway that alters the expression of genes involved in colon cancer growth. In our earlier studies on global gene expression with cDNA microarrays, we have shown that treatment of CaCo-2 colon cancer cells with docosahexaenoic acid (DHA) down-regulated the prostaglandin family of genes, as well as cyclooxygenase 2 expression and several cell cycle-related genes, whereas it up-regulated caspases 5, 8, 9, and 10 that are associated with apoptosis. It is known that nitric oxide activates the cyclooxygenase 2 enzyme, which plays a pivotal role in the progression of colon cancer via prostaglandin synthesis and angiogenesis. The present study was undertaken to examine the multifaceted role of DHA in the expression of inducible nitric oxide synthase (iNOS) and of related proinflammatory genes, as those have been shown to play a role in tumor progression. In addition, we aimed to identify associated target genes by DNA microarray, reverse transcription-PCR analysis, and cellular localization of iNOS expression in CaCo-2 cells. Results of this study demonstrate that treatment with DHA down-regulates iNOS in parallel with a differential expression and down-regulation of IFNs, cyclic GMP, and nuclear factor kappa B isoforms. More importantly, our findings clearly demonstrate the up-regulation of cyclin-dependent kinase inhibitors p21((Waf1/Cip1)) and p27, differentiation-associated genes such as alkaline phosphatases, and neuronal differentiation factors. These finding strongly suggest that the antitumor activity of DHA may be attributed, at least in part, to an effect on iNOS regulatory genes. In addition, our results indicate the presence of specific gene expression profiles in human colon cancer that can be used as molecular targets for chemopreventive agents.
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PMID:Modulation of inducible nitric oxide synthase and related proinflammatory genes by the omega-3 fatty acid docosahexaenoic acid in human colon cancer cells. 1261 11

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

Nitric oxide (NO)-releasing aspirin (ASA), consisting of a traditional ASA molecule to which a NO-donating moiety is covalently bound, is a promising colon cancer chemopreventive agent. NO-ASA inhibits colon cancer cell growth more potently than ASA by inhibiting cell proliferation and enhancing cell killing. We examined in cultured human colon cancer cells the effect of NO-ASA on the beta-catenin/T-cell factor signaling pathway, nuclear factor-kappaB, and NO synthase 2 and on cyclooxygenase (COX) expression, all presumed to participate in colon carcinogenesis. Besides inhibiting cell growth, NO-ASA inhibited the beta-catenin/T-cell factor signaling pathway (IC(50), 1.1 microM), nuclear factor-kappaB DNA binding (IC(50), 7.5 microM), and NO synthase 2 expression (IC(50), 2 microM). Interestingly, NO-ASA induced COX-2 expression, although it had no effect on COX-1. COX-2 induction was accompanied by increased prostaglandin E(2) production. These effects occurred at NO-ASA concentrations below or near its IC(50) for cell growth (IC(50), 2-50 microM). The metabolism of NO-ASA by these cells is characterized by a rapid deacetylation step and the formation of a conjugate with glutathione. NO-ASA had no effect on intracellular cyclic GMP concentrations. We propose a model incorporating the pleiotropic effects of NO-ASA on cell signaling and postulate that collectively these effects may contribute to its strong chemopreventive effect.
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PMID:Growth inhibition of human colon cancer cells by nitric oxide (NO)-donating aspirin is associated with cyclooxygenase-2 induction and beta-catenin/T-cell factor signaling, nuclear factor-kappaB, and NO synthase 2 inhibition: implications for chemoprevention. 1463 77

The activation of protein kinase G (PKG) by cGMP has become of considerable interest as a novel molecular mechanism for the induction of apoptosis in cancer cells, because sulindac sulfone (exisulind, Aptosyn) and certain derivatives that inhibit cGMP-phosphodiesterases and thereby increase cellular levels of cGMP appear to induce apoptosis via this mechanism. However, other effects of these compounds have not been excluded, and the precise mechanism by which PKG activation induces apoptosis has not been elucidated in detail. To directly examine the effects of PKG on cell growth and apoptosis, we generated a series of mutants of PKG Ialpha: PKG IalphaS65D, a constitutively activated point mutant; PKG IalphaDelta, a constitutively activated N-terminal truncated mutant; and PKG IalphaK390R, a dominant-negative point mutant. A similar series of mutants of PKG Ibeta were also constructed (Deguchi et al., Mol. Cancer Ther., 1: 803-809, 2002). The present study demonstrates that when transiently expressed in SW480 colon cancer, the constitutively activated mutants of PKG Ibeta, and to a lesser extent PKG Ialpha, inhibit colony formation and induce apoptosis. We were not able to obtain derivatives of SW480 cells that stably expressed these constitutively activated mutants, presumably because of toxicity. However, derivatives that stably overexpressed wild-type PKG Ibeta displayed growth inhibition, whereas derivatives that stably expressed the dominant-negative mutant (KR) of PKG Ibeta grew more rapidly and were more resistant to Aptosyn-induced growth inhibition than vector control cells. Stable overexpression of PKG Ibeta was associated with decreased cellular levels of beta-catenin and cyclin D1 and increased levels of p21(CIP1). Reporter assays indicated that activation of PKG Ibeta inhibits the transcriptional activity of the cyclin D1 promoter. We also found that transient expression of the constitutively activated mutants of PKG Ibeta inhibited cell migration. Taken together, these results indicate that activation of PKG Ibeta is sufficient to inhibit growth and cell migration and induce apoptosis in human colon cancer cells and that these effects are associated with inhibition of the transcription of cyclin D1 and an increase in the expression of p21(CIP1).
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PMID:Activation of protein kinase G is sufficient to induce apoptosis and inhibit cell migration in colon cancer cells. 1517 9

Guanylyl cyclase C and accumulation of cGMP induced by bacterial heat-stable enterotoxins (STs) promote colon cancer cell cytostasis, serving as a tumor suppressor in intestine. Conversely, capacitative calcium entry through store-operated calcium channels (SOCs) is a key signaling mechanism that promotes colon cancer cell proliferation. The present study revealed that proliferative signaling by capacitative calcium entry through SOCs opposes and is reciprocally coupled to cytostasis mediated by guanylyl cyclase C in T84 human colon carcinoma cells. Elimination of capacitative calcium entry employing 2-aminoethoxydiphenylborate (2-APB), a selective inhibitor of SOCs, potentiated cytostasis induced by ST. Opposition of ST-induced cytostasis by capacitative calcium entry reflects reciprocal inhibition of guanylyl cyclase C signaling. Calcium entry through SOCs induced by the calcium-ATPase inhibitor thapsigargin or the receptor agonists UTP or carbachol inhibited guanylyl cyclase C-dependent cGMP accumulation. This effect was mimicked by the calcium ionophore ionomycin and blocked by 2-APB and intracellular 1,2-bis(o-amino-5,5'-dibromophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM), a chelator of calcium. Moreover, regulation by capacitative calcium entry reflected ligand-dependent sensitization of guanylyl cyclase C to inhibition by that cation. Although basal catalytic activity was refractory, ST-stimulated guanylyl cyclase C was inhibited by calcium, which antagonized binding of magnesium to allosteric sites required for receptor-effector coupling. These observations demonstrate that reciprocal regulation of guanylyl cyclase C signaling by capacitative calcium entry through SOCs represents one limb of a coordinated mechanism balancing colon cancer cell proliferation and cytostasis. They suggest that combining guanylyl cyclase C agonists and SOC inhibitors offers a novel paradigm for cGMP-directed therapy and prevention for colorectal tumors.
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PMID:Proliferative signaling by store-operated calcium channels opposes colon cancer cell cytostasis induced by bacterial enterotoxins. 1593 49

We recently reported that proteinase-activated receptors type I (PAR-1) are coupled to both negative and positive invasion pathways in colonic and kidney cancer cells cultured on collagen type I gels. Here, we found that treatments with the cell-permeant analog 8-Br-cGMP and the soluble guanylate cyclase activator BAY41-2272, and Rho kinase (ROK) inhibition by Y27632 or a dominant negative form of ROK lead to PAR-1-mediated invasion through differential Rac1 and Cdc42 signaling. Hypoxia or the counteradhesive matricellular protein SPARC/BM-40 (SPARC: secreted protein acidic rich in cysteine) overexpressed during cancer progression also commutated PAR-1 to cellular invasion through the cGMP/protein kinase G (PKG) cascade, RhoA inactivation, and Rac1-dependent or -independent signaling. Cultured primary cancer cells isolated from peritoneal and pleural effusions from patients with colon cancer or other malignant tumors harbored PAR-1, as shown by RT-PCR and FACS analyses. These malignant effusions also contained high levels of activated thrombin and fibrin, and induced a proinvasive response in HCT8/S11 human colorectal cancer cells. Our data underline the essential role of the tumor microenvironment and of several commutators targeting cGMP/PKG signaling and the RhoA-ROK axis in the control of PAR-1 proinvasive activity and metastatic potential of cancer cells in distant organs and peritoneal or pleural cavities. We also add new insights into the mechanisms linking the coagulation mediators thrombin and PAR-1 in the context of blood coagulation disorders and venous thrombosis often observed in cancer patients, as described in 1865 by Armand Trousseau.
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PMID:Commutators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho-Rho kinase axis and tumor microenvironment. 1609 33

Recent studies indicate that the induction of apoptosis in human colon cancer cells by certain nonsteroidal antiinflammatory drugs involves increased expression of 15-LOX-1 and synthesis of its major product 13-S-hydroxyoctadecadienoic acid (13-S-HODE). Evidence was obtained that this occurs via a cyclooxygenase-2 (COX-2)-independent mechanism, but the actual mechanism of induction of 15-LOX-1 by these compounds is not known. There is extensive evidence that treatment of SW480 human colon cancer cells with sulindac sulfone (Exisulind, Aptosyn) or the related derivative OSI-461, both of which inhibit cyclic GMP (cGMP)-phosphodiesterases but lack COX-2 inhibitory activity, causes an increase in intracellular levels of cGMP, thus activating protein kinase G (PKG), which then activates pathways that lead to apoptosis. Therefore, in the present study, we examined the effects of various agents that cause increased cellular levels of cGMP on the expression of 15-LOX-1 in SW480 human colon cancer cells. Treatment of the cells with Exisulind, sulindac sulfide, OSI-461, the guanylyl cyclase activator YC-1, or the cell-permeable cGMP compound 8-para-chlorophenylthio-cGMP (8-pCPT-cGMP) caused an increase in cellular levels of 15-LOX-1. Exisulind, OSI-461, and 8-pCPT-cGMP also increased mRNA levels of 15-LOX-1, suggesting that the effects were at the level of transcription. The cGMP-phosphodiesterase inhibitors and YC-1 increased the production of 13-S-HODE, which is the linoleic acid metabolite of 15-LOX-1. Treatment of SW480 cells with the PKG inhibitor Rp-8-pCPT-cGMP blocked Exisulind-induced 15-LOX-1 expression. Furthermore, derivatives of SW480 cells that were engineered to stably overexpress wild-type PKG Ibeta displayed increased cellular levels of 15-LOX-1 when compared with vector control cells. Taken together, these results provide evidence that the cGMP/PKG pathway can play an important role in the induction of 15-LOX-1 expression by nonsteroidal antiinflammatory drugs and related agents.
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PMID:Activation of protein kinase G up-regulates expression of 15-lipoxygenase-1 in human colon cancer cells. 1616 23

Bacterial diarrheagenic heat-stable enterotoxins induce colon cancer cell cytostasis by targeting guanylyl cyclase C (GCC) signaling. Anticancer actions of these toxins are mediated by cyclic guanosine 3',5'-monophosphate (cGMP)-dependent influx of Ca2+ through cyclic nucleotide-gated channels. However, prolonged stimulation of GCC produces resistance in tumor cells to heat-stable enterotoxin-induced cytostasis. Resistance reflects rapid (tachyphylaxis) and slow (bradyphylaxis) mechanisms of desensitization induced by cGMP. Tachyphylaxis is mediated by cGMP-dependent protein kinase, which limits the conductance of cyclic nucleotide-gated channels, reducing the influx of Ca2+ propagating the antiproliferative signal from the membrane to the nucleus. In contrast, bradyphylaxis is mediated by cGMP-dependent allosteric activation of phosphodiesterase 5, which shapes the amplitude and duration of heat-stable enterotoxin-dependent cyclic nucleotide accumulation required for cytostasis. Importantly, interruption of tachyphylaxis and bradyphylaxis restores cancer cell cytostasis induced by heat-stable enterotoxins. Thus, regimens that incorporate cytostatic bacterial enterotoxins and inhibitors of cGMP-mediated desensitization offer a previously unrecognized therapeutic paradigm for treatment and prevention of colorectal cancer.
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PMID:Interruption of homologous desensitization in cyclic guanosine 3',5'-monophosphate signaling restores colon cancer cytostasis by bacterial enterotoxins. 1632 63

Colorectal cancer is the second leading cause of cancer mortality in the United States. Substantial human and animal data support the ability of nonsteroidal anti-inflammatory drugs to cause regression of existing colon tumors and prevent new tumor formation. The mechanism by which the nonsteroidal anti-inflammatory drug sulindac prevents tumor growth is poorly understood and seems complex as sulindac can modulate several growth-related signaling pathways. Sulindac metabolites simultaneously (a) increase cellular cyclic GMP and subsequently activate cyclic GMP-dependent protein kinase (PKG); (b) activate c-jun NH2-terminal kinase (JNK); (c) inhibit extracellular signal-regulated kinase 1/2 (ERK1/2); and (d) decrease beta-catenin protein expression at times and doses consistent with apoptosis. The purpose of this study was to determine if PKG, ERK1/2, JNK, and beta-catenin are independent targets for sulindac in vitro. Pharmacologic activation of PKG with YC-1 increases JNK phosphorylation and induces apoptosis in colon cancer cells without modulating ERK1/2 phosphorylation or beta-catenin protein expression. Inhibition of ERK1/2 with U0126 induces apoptosis but fails to activate JNK phosphorylation or down-regulate beta-catenin protein expression. Cotreatment with U0126 and YC-1 synergistically increases apoptosis in colorectal cancer cells and recapitulates the effects of sulindac treatment on ERK1/2, JNK, and beta-catenin. These results indicate that sulindac metabolites modulate ERK1/2 and PKG pathways independently in colon cancer cells and suggest that the full apoptotic effect of sulindac is mediated by more than one pathway. Using similar combinatorial approaches in vivo may provide more effective, less toxic chemopreventive and chemotherapeutic strategies. Such therapies could dramatically reduce the incidence and death rate from colorectal cancer.
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PMID:Sulindac independently modulates extracellular signal-regulated kinase 1/2 and cyclic GMP-dependent protein kinase signaling pathways. 1654 90

The nonsteroidal anti-inflammatory drug sulindac is metabolized to sulindac sulfone (exisulind), an antineoplastic agent that inhibits growth and induces apoptosis in solid tumors. In colon cancer cells, the antineoplastic effects of exisulind have been attributed, in part, to induction of cyclic guanosine 3',5'-monophosphate (cGMP) signaling through inhibition of cGMP-specific phosphodiesterases, which elevates intracellular cGMP, and novel expression of cGMP-dependent protein kinase (PKG) Ibeta, the presumed downstream effector mediating apoptosis. Here, inhibition of proliferation and induction of cell death by exisulind was dissociated from cGMP signaling in human colon cancer cells. Accumulation of intracellular cGMP produced by an exogenous cell-permeant analogue of cGMP or a potent agonist of guanylyl cyclase C yielded cytostasis without cell death. Surprisingly, the antiproliferative effects of induced cGMP accumulation were paradoxically less than additive, rather than synergistic, when combined with exisulind. Further, although exisulind induced expression of PKG Ibeta, it did not elevate intracellular cGMP and its efficacy was not altered by inhibition or activation of PKG I. Rather, PKG I induced by exisulind may mediate desensitization of cytostasis induced by cGMP. Thus, cytotoxic effects of exisulind are independent of cGMP signaling in human colon cancer cells. Moreover, combination therapies, including exisulind and agents that induce cGMP signaling, may require careful evaluation in patients with colon cancer.
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PMID:Exisulind and guanylyl cyclase C induce distinct antineoplastic signaling mechanisms in human colon cancer cells. 1673 51


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