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)

Cox-2 plays an important role in colon carcinogenesis and inflammation. Studying the HT-29 colon cancer cell line as a model, we found that Cox-2 expression and activity is increased approximately 25-fold by TNF-alpha. As previously reported for other Cox-2 inducers, this activation appears to result from a p38-mediated mRNA stabilization rather than an increase in promoter activity. The HDAC inhibitors butyrate and TSA blocked the TNF-alpha activation of Cox-2 protein and mRNA synthesis, and dramatically suppressed Cox-2 activity in HT-29 cells. The suppression of Cox-2 synthesis did not involve promoter inactivation and could be achieved even when applied after the TNF-alpha stimulus. The effect of the HDAC inhibitors was observed prior to the activation of p21 expression and did not require new protein synthesis. Finally, butyrate did not prevent p38 phosphorylation, so the block is likely to occur at a later step in the activation pathway. We propose that a component of the cytokine-induced Cox-2 mRNA stabilization pathway is sensitive to acetylation.
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PMID:Butyrate suppresses Cox-2 activation in colon cancer cells through HDAC inhibition. 1506 80

We recently reported that cAMP suppresses apoptosis in colon cancer cells and induces cellular inhibitor of apoptosis protein-2 (c-IAP2) via a cAMP-responsive element (CRE), suggesting a mechanism for chemoprevention of colon cancer by non-steroidal anti-inflammatory drugs. In this study, we used T84 human colon cancer cells to define the pathway by which increases in cAMP induce c-IAP2 expression. Treatment with several different cAMP agonists stimulated phosphorylation of CRE-binding protein (CREB) and activated expression of c-IAP2 in a CREB-dependent manner. Studies with pharmacological inhibitors revealed that cAMP-dependent phosphorylation of CREB required activation of ERK1/2 and p38 MAPK but was largely independent of protein kinase A. Immunoblots and transcriptional reporter assays using specific inhibitors, as well as expression of constitutively active forms of MEK1 and MKK3, showed that c-IAP2 induction by cAMP is regulated predominantly through ERK1/2 and p38 MAPK and suggested involvement of p90 ribosomal protein S6 kinase and mitogen and stress response kinase-1 as well. Consistent with those results, we found that cAMP-dependent suppression of apoptosis was blocked by treatment with inhibitors of ERK1/2 and p38 MAPK. We conclude that cAMP can induce c-IAP2 expression in colon cancer cells through CREB phosphorylation and CRE-dependent transcription in a manner that involves activation of ERK1/2 and p38 MAPK. These results emphasize that activation of kinases other than protein kinase A can mediate the actions of agents that increase cAMP, particularly in the regulation of CREB-dependent events.
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PMID:Cyclic AMP promotes cAMP-responsive element-binding protein-dependent induction of cellular inhibitor of apoptosis protein-2 and suppresses apoptosis of colon cancer cells through ERK1/2 and p38 MAPK. 1507 90

Curcumin, the major pigment of the dietary spice turmeric has the potential for chemoprevention by promotion of apoptosis. Mitogen-activated protein kinase (MAPK) and NF-kappa B (NFkappaB) signalling cascades are thought to regulate apoptosis and cell survival. While curcumin inhibits NFkappaB, its effects upon the MAPK pathways are unclear. This study investigates curcumin effects upon MAPK signalling and apoptosis in HCT116 cells. Here we report that curcumin time- and dose-dependent induction of apoptosis were accompanied by sustained phosphorylation and activation of c-jun N-terminal kinase (JNK) and p38 MAPK as well as inhibition of constitutive NFkappaB transcriptional activity. Curcumin treatment also induced JNK-dependent sustained phosphorylation of c-jun and stimulation of AP-1 transcriptional activity. Curcumin-mediated c-jun phosphorylation and apoptosis were reduced by treatment with the JNK-specific inhibitor SP600125. Conversely, the p38-specific inhibitor SB203580 had no effect upon curcumin-induced apoptosis. Curcumin treatment had no effect on the activity of extracellular signal-regulated protein kinase (ERK). Taken together, our data show for the first time that JNK, but not p38 or ERK signalling, plays an important role in curcumin-mediated apoptosis in human colon cancer cells that may underlie its chemopreventive effects.
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PMID:Curcumin induces c-jun N-terminal kinase-dependent apoptosis in HCT116 human colon cancer cells. 1525 84

Ent-11 alpha-hydroxy-15-oxo-kaur-16-en-19-oic-acid (5F), an antitumor component, is a chemical compound isolated from Pteris semipinnata L (PsL), a Chinese traditional herb. We examined whether 5F could affect apoptosis in human colon cancer HT-29 cells, and test whether and how the over-expression of Bcl-2 and Bcl-xL could offset the effect of 5F on cell growth. The result demonstrated that 5F significantly induced apoptosis of HT-29, as shown by MTT assay and DNA fragmentation measurement. Treatment of HT-29 with 5F increased both p38 and iNOS levels, suggesting these two molecules may contribute to the apoptotic effect of 5F. Over-expression of Bcl-2 or Bcl-xL attenuated the increase of p38 and iNOS induced by 5F. The cells with Bcl-2 or Bcl-xL over-expression showed an elevation of nuclear factor kappa B (NF-kappa B) activity, accompanying a significant reduction of 5F-induced apoptosis. Furthermore, inhibition of NF-kappa B by I k B alpha SR, which is a powerful inhibitor of NF-kappa B, restored the ability of 5F to induce apoptosis in the cells transfected with Bcl-2. These data strongly indicated that the apoptotic effect of 5F on HT-29 was closely associated with the activity of NF-kappa B, which was up-regulated by Bcl-2 and Bcl-xL. In conclusion, 5F induced apoptosis in HT-29 cells and this apoptotic effect was associated with the high level of p38 and iNOS expression. The apoptotic effect of 5F could be significantly offset by over-expression of either Bcl-2 or Bcl-xL. Bcl-2, and to the less extent, Bcl-xL, were able to increase the activity of NF-kappa B, which was a known anti-apoptotic molecule in human colon cancer cells.
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PMID:Over-expression of Bcl-2 against Pteris semipinnata L-induced apoptosis of human colon cancer cells via a NF-kappa B-related pathway. 1531 90

Previously, we have demonstrated that the butyrate-induced differentiation in the human colon cancer cell line Caco-2 occurs via upregulation of the vitamin D receptor (VDR). However, the downstream pathways involved are unknown. The mitogen-activated protein kinases (MAPKs) have been shown to play an important role in regulation of cell differentiation, and may therefore be a potential target of butyrate action. To assess their role in butyrate-mediated cell differentiation and VDR expression, we used the specific p38-MAPK inhibitor SB203580 and the ERK1/2 MAPK-inhibitor PD98059. The p38-MAPK inhibitor abolished the butyrate effect on VDR expression and cell differentiation, while the ERK1/2 inhibitor did not influence the butyrate-mediated induction of cell differentiation and VDR expression. The essential role of the p38 pathway in up-regulation of VDR expression was further confirmed by using the p38 stimulator arsenite. These results imply an important role of the p38-MAPK in regulation of cellular differentiation through upregulation of VDR expression by butyrate.
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PMID:p38 MAPK signaling pathway is involved in butyrate-induced vitamin D receptor expression. 1550 45

The nonsteroidal anti-inflammatory drug (NSAID) sulindac prevents experimental colon cancer and can regress precancerous polyps in humans. Sulindac sulfide inhibits cyclooxygenase (COX)-mediated prostaglandin synthesis and retards the growth of cultured colon cell lines primarily by inducing apoptosis. Given the known role of mitogen-activated protein kinase (MAPK) in signal transduction and the regulation of cell survival and death, we determined the effect of sulindac sulfide on MAPK activation, COX-2 expression, and apoptosis induction in HCA-7 human colon cancer cells. Sulindac sulfide treatment was associated with activation of ERKp44/42 and p38 MAPK in a dosage- and time-dependent manner, and also activated upstream MEK. Similar results were seen in HCT-15 cells and also with the selective COX-2 inhibitor NS398. ERKp44/42 and p38 activation were accompanied by an induction of COX-2 protein expression. Selective inhibitors of sulindac sulfide-induced ERKp44/42 (PD98059) and p38 MAPK (SB203580) activation also suppressed the induction of COX-2 by this NSAID. Furthermore, both MAPK inhibitors significantly augmented sulindac sulfide-induced apoptosis, as did suppression of constitutive COX-2 using antisense oligonucleotides. In conclusion, MEK/ERK and p38 MAPK activation mediate COX-2 induction by sulindac sulfide. Selective inhibitors of these MAPKs potentiate apoptosis induction by this NSAID, suggesting a novel strategy for the prevention or treatment of colorectal cancer.
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PMID:Selective inhibitors of MEK1/ERK44/42 and p38 mitogen-activated protein kinases potentiate apoptosis induction by sulindac sulfide in human colon carcinoma cells. 1565 53

MAPK cascades play the critical role in regulating Ras oncogene activity by phosphorylation-dependent mechanisms. Whereas the ERK MAPK pathway is required for Ras transformation, our previous works established that the p38 activity is inhibitory to Ras signaling in both experimental and ras-mutated cancer cells (Chen, G., Hitomi, M., Han, J., and Stacey, D. W. (2000) J. Biol. Chem. 275, 38973-38980; Qi, X., Tang, J., Pramanik, R., Schultz, R. M., Shirasawa, S., Sasazuki, T., Han, J., and Chen, G. (2004) J. Biol. Chem., 279, 22138-22144). Here we report that K-Ras activated p38gamma, a p38 MAPK family member, by inducing its expression without increasing its phosphorylation and that depletion of induced p38gamma suppressed Ras transformation in rat intestinal epithelial cells. This p38gamma activity contrasts with that of its family member, p38alpha, which is activated by Ras through phosphorylation, leading to an inhibition of Ras transformation. Mechanistic analyses showed that unphosphorylated p38gamma may promote Ras transformation through an increased complex formation with ERK proteins. Significantly, functional p38gamma protein was expressed only in K-ras-mutated human colon cancer cells, and p38gamma transcripts were ubiquitously increased in a set of primary human colon cancer tissues. These studies thus demonstrate the essential role of p38gamma in K-Ras transformation independent of phosphorylation, and elevated p38gamma may serve as a novel diagnostic marker and therapeutic target for human colon cancer.
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PMID:Essential role of p38gamma in K-Ras transformation independent of phosphorylation. 1585 77

Although expression of the gastrin/cholecystokinin-2 receptor (CCK2R) is widely reported in human colorectal cancer, little is known on its role in mediating mature amidated gastrin (gastrin-17 amide, G-17) induced intracellular signal transduction in colon cancer cells. The purpose of this study was to explore the intracellular events of colorectal cancer cells after gastrin binding to CCK2R. Meanwhile, the influence of a natural point mutation 286V-->F in the third intracellular loop of CCK2R on gastrin-envoked intracellular signal transduction was also investigated. Firstly, Colo320 cells were stably transfected with wild type (Colo320 WT) and mutant CCK2R (Colo320 M), respectively. The intracellular signal transduction events in response to gastrin were investigated in both Colo320 WT and Colo320 M cells. In Colo320 WT cells, G-17 induced formation of intracellular cyclic AMP and inositol 1,4,5-trisphosphate, and stimulated intracellular calcium mobilization. G-17 also stimulated tyrosine phosphorylation of ERKl/2, p38, FAK, and paxillin, and up-regulated the mRNA expression of early response gene c-Jun and c-Fos. However, G-17 inhibited proliferation and induced apoptosis in Colo320 WT cells. Mutation 286V-->F in the third intracellular loop of CCK2R blocked G-17 induced biological without affecting binding affinity of CCK2R to G-17. Our results suggest that activation of CCK2R by gastrin stimulates heterotrimeric G-protein Gq and G(12/13) mediated intracellular signal transduction pathway in colon cancer cells. The valine-287 residue in third intracellular loop of CCK2R plays a pivotal role in CCK2R mediated intracellular signal transduction.
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PMID:Valine-286 residue in the third intracellular loop of the cholecystokinin 2 receptor exerts a pivotal role in cholecystokinin 2 receptor mediated intracellular signal transduction in human colon cancer cells. 1595 Nov 56

The phytochemical 11,11'-dideoxyverticillin, derived from the fungus Shiraia bambusicola, has been shown to possess potent anticancer activity in vitro and in vivo. Here, we investigated the effect of 11,11'-dideoxyverticillin on cell cycle progression, and explored the potential mechanisms for this effect. A concentration- and time-dependent cell cycle blockade at G2/M phase was observed in human colon cancer cells (HCT-116) following 11,11'-dideoxyverticillin treatment and was associated with marked increases in levels of p53, phospho-p53(ser20) and phospho-Chk2(Thr 68). When wild type p53 expression was specifically inhibited by RNA interference, HCT-116 cells treated with 11,11'-dideoxyverticillin failed to arrest in G2/M and did not show increased phospho-Chk2(Thr 68). On the other hand, 11,11'-dideoxyverticillin treatment also elicited p38 MAP kinase activity and expression of phospho-p38 MAPK. Treatment with a specific p38 MAPK inhibitor (SB203580) successfully inhibited p38 MAPK and delayed the onset of G2/M arrest induced by 0.5 microM 11,11'-dideoxyverticillin after approximately 6 h, but did not abolish the induction of G2/M arrest. Additionally, SB203580 did not alter the levels of p53, phospho-p53 (ser20), or phospho-Chk2 (Thr68) proteins in 11,11'-dideoxyverticillin-treated cells. Together, these findings indicate that p53-mediated phosphorylation of Chk2 maybe plays a vital role in 11,11'-dideoxyverticillin-induced G2/M arrest, and that p38 MAPK might accelerate this progression. Our work suggests a new possibility of interactions among p53, Chk2 and p38 MAPK signaling in G2/M arrest.
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PMID:The p53 pathway is synergized by p38 MAPK signaling to mediate 11,11'-dideoxyverticillin-induced G2/M arrest. 1596 7

It is well documented that prolonged inflammatory conditions, particularly those relating to the colon, have been shown to induce cancer. We have previously demonstrated that the pro-inflammatory mediator leukotriene D(4) (LTD(4)) induces survival and proliferation in intestinal cells and that its receptor, CysLT(1), is upregulated in human colon cancer tissue. Here we demonstrate, for the first time that in both Int 407 (a non-transformed human intestinal epithelial cell line) and Caco-2 cells (a human colorectal carcinoma cell line), cytosolic phospholipase A(2)alpha (cPLA(2)alpha) is activated and translocates to the nucleus upon LTD(4) stimulation via a calcium-dependent mechanism that involves activation of protein kinase C (PKC), and the mitogen-activated protein kinases ERK1/2 and p38. We also show with a cPLA(2)alpha promoter luciferase assay, that LTD(4) induces an increase in the transcriptional activity of cPLA(2)alpha via activation of cPLA(2)alpha and the transcription factor NFkappaB. Interestingly we demonstrate here that both the basal and the LTD(4)-induced cPLA(2)alpha activity is elevated approximately 3-fold in Caco-2 colon cancer cells compared with Int 407 cells. The difference in basal activity was confirmed in human colon tumor samples by the finding of a similar increase in cPLA(2)alpha activity when compared with normal colon tissue. A functional role of the increased cPLA(2)alpha activity in tumor cells was revealed by our findings that inhibition of this enzyme reduced both basal and LTD(4)-induced proliferation, the effects being most pronounced in Caco-2 tumor cells. The present data reveal that cPLA(2)alpha, an important intracellular signal activated by inflammatory mediators, is an important regulator of colon tumor growth.
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PMID:Activation of cPLA2 is required for leukotriene D4-induced proliferation in colon cancer cells. 1597 62


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