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

Alkaline sphingomyelinase (alk-SMase) is a new member of the NPP (nucleotide pyrophosphatase/phosphodiesterase) family that hydrolyses SM (sphingomyelin) to generate ceramide in the intestinal tract. The enzyme may protect the intestinal mucosa from inflammation and tumorigenesis. PAF (platelet-activating factor) is a pro-inflammatory phospholipid involved in pathogenesis of inflammatory bowel diseases. We examined whether alk-SMase can hydrolyse and inactivate PAF. [3H]Octadecyl-labelled PAF was incubated with purified rat intestinal alk-SMase or recombinant human alk-SMase expressed in COS-7 cells. The hydrolytic products were assayed with TLC and MS. We found that alkSMase cleaved the phosphocholine head group from PAF and generated 1-O-alkyl-2-acetyl-sn-glycerol. Differing from the activity against SM, the activity against PAF was optimal at pH 7.5, inhibited by EDTA and stimulated by 0.1-0.25 mM Zn2+. The activity was abolished by site mutation of the predicted metal-binding sites that are conserved in all NPP members. Similar to the activity against SM, the activity against PAF was dependent on bile salt, particularly taurocholate and taurochenodeoxycholate. The V(max) for PAF hydrolysis was 374 mumol x h(-1) x (mg of protein)(-1). The hydrolysis of PAF and SM could be inhibited by the presence of SM and PAF respectively, the inhibition of PAF hydrolysis by SM being stronger. The PAF-induced MAPK (mitogen-activated protein kinase) activation and IL-8 (interleukin 8) release in HT-29 cells, and chemotaxis in leucocytes were abolished by alk-SMase treatment. In conclusion, alk-SMase hydrolyses and inactivates PAF by a phospholipase C activity. The finding reveals a novel function, by which alk-SMase may counteract the development of intestinal inflammation and colon cancer.
 ...
PMID:Intestinal alkaline sphingomyelinase hydrolyses and inactivates platelet-activating factor by a phospholipase C activity. 1625 17

Glycogen-synthase kinase-3 (GSK-3) and extracellular signal-regulated kinase (ERK) are critical downstream signaling proteins for the PI3-kinase/Akt and Ras/Raf/MEK-1 pathway, respectively, and regulate diverse cellular processes including embryonic development, cell differentiation and apoptosis. Here, we show that inhibition of GSK-3 using GSK-3 inhibitors or RNA interference (RNAi) significantly induced the phosphorylation of ERK1/2 in human colon cancer cell lines HT29 and Caco-2. Pretreatment with the PKCdelta-selective inhibitor rottlerin or transfection with PKCdelta siRNA attenuated the phosphorylation of ERK1/2 induced by the GSK-3 inhibitor SB-216763 and, furthermore, treatment with SB-216763 or transfection with GSK-3alpha and GSK-3beta siRNA increased PKCdelta activity, thus identifying a role for PKCdelta in the induction of ERK1/2 phosphorylation by GSK-3 inhibition. Treatment with SB-216763 increased expression of cyclooxygenase-2 (COX-2) and IL-8, which are downstream targets of ERK1/2 activation; this induction was abolished by MEK/ERK inhibition, suggesting GSK-3 inhibition induced COX-2 and IL-8 through ERK1/2 activation. The transcriptional induction of COX-2 and IL-8 by GSK-3 inhibition was further demonstrated by the increased COX-2 and IL-8 promoter activity after SB-216763 treatment or transfection with GSK-3alpha or GSK-3beta siRNA. Importantly, our findings identify GSK-3, acting through PKCdelta, as a negative regulator of ERK1/2, thus revealing a novel crosstalk mechanism between these critical signaling pathways.
 ...
PMID:Glycogen synthase kinase-3 is a negative regulator of extracellular signal-regulated kinase. 1627 84

Saccharomyces boulardii is gaining in popularity as a treatment for a variety of diarrheal diseases as well as inflammatory bowel disease. This study was designed to examine the effect of this yeast on infection by Shigella flexneri, a highly infectious and human host-adapted enteric pathogen. We investigated key interactions between the bacteria and host cells in the presence of the yeast in addition to a number of host responses including proinflammatory events and markers. Although the presence of the yeast during infection did not alter the number of bacteria that was able to attach or invade human colon cancer-derived T-84 cells, it did positively impact the tight junction protein zonula occluden-2 and significantly increase the barrier integrity of model epithelia. The yeast also decreased ERK, JNK, and NF-kappaB activation in response to S. flexneri, events likely responsible for the observed reductions in IL-8 secretion and the transepithelial migration of polymorphonuclear leukocytes across T-84 monolayers. These results, suggesting that the yeast allowed for a dampened inflammatory response, were confirmed in vivo utilizing a highly relevant model of human fetal colonic tissue transplanted into scid mice. Furthermore, a cell-free S. boulardii culture supernatant was also capable of reducing IL-8 secretion by infected T-84 cells. These data suggest that although the use of S. boulardii during infection with S. flexneri may alleviate symptoms associated with the inflammatory response of the host, it would not prevent infection.
 ...
PMID:Saccharomyces boulardii interferes with Shigella pathogenesis by postinvasion signaling events. 1803 77

Ghrelin is a growth hormone-releasing peptide, discovered in 1999 by Kojima et al. Its potential role in inflammation and stress response is not yet clear. The purpose of this study was to characterize perioperative levels of circulating ghrelin in relation to different surgical procedures. The authors compared plasma ghrelin changes with cortisol, cytokines, and acute-phase proteins. The prospective study was performed on 22 patients with resection for colon cancer (group 1). Group 2, functioning as a comparative group, consisted of 22 patients with elective laparotomic cholecystectomy. Plasma concentrations of ghrelin, cortisol, tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta, IL-6, IL-8, soluble IL-2 receptor, C reactive protein, and alpha1-antitrypsin were estimated repeatedly during a 72-hour postoperative period. Data revealed significant elevation of plasma ghrelin 24 hours after resection of coli (median 508.0 ng/l, interquartile range 398.2-633.7 ng/l) in relation to both preoperative levels (317.6 ng/l, 253.4-355.1 ng/l, p<0.01) and group 2 maximal postoperative levels (386.2 ng/l, 324-432 ng/l, p<0.05). Ghrelin levels returned to initial status 36-48 hours after surgery with subsequent decline to subnormal levels. The regression coefficient was the highest for ghrelin and TNF-alpha 24 hours after laparotomy (r=0.64, p<0.05) and for ghrelin and IL-6 24 hours after surgery (r=0.56, p<0.05). Maximal postoperative levels of all tested parameters except for cortisol and IL-1beta differed significantly between both patient groups at p<0.05. After large abdominal surgery, ghrelin shows itself as an acute-phase reactant. The significant correlation between ghrelin and inflammatory cytokines supposes their regulatory role in this period. Our comparison of more- and less-invasive surgical procedures with similar nutritional restrictions argues for a dominant role of inflammatory factors in postoperative ghrelin elevation.
 ...
PMID:Ghrelin as an acute-phase reactant during postoperative stress response. 1840 98

RNA-binding proteins play a key role in post-transcriptional regulation of mRNA stability and translation. We have identified that RBM3, a translation regulatory protein, is significantly upregulated in human tumors, including a stage-dependent increase in colorectal tumors. Forced RBM3 overexpression in NIH3T3 mouse fibroblasts and SW480 human colon epithelial cells increases cell proliferation and development of compact multicellular spheroids in soft agar suggesting the ability to induce anchorage-independent growth. In contrast, downregulating RBM3 in HCT116 colon cancer cells with specific siRNA decreases cell growth in culture, which was partially overcome when treated with prostaglandin E(2), a product of cyclooxygenase (COX)-2 enzyme activity. Knockdown also resulted in the growth arrest of tumor xenografts. We have also identified that RBM3 knockdown increases caspase-mediated apoptosis coupled with nuclear cyclin B1, and phosphorylated Cdc25c, Chk1 and Chk2 kinases, implying that under conditions of RBM3 downregulation, cells undergo mitotic catastrophe. RBM3 enhances COX-2, IL-8 and VEGF mRNA stability and translation. Conversely, RBM3 knockdown results in loss in the translation of these transcripts. These data demonstrate that the RNA stabilizing and translation regulatory protein RBM3 is a novel proto-oncogene that induces transformation when overexpressed and is essential for cells to progress through mitosis.
 ...
PMID:Translation regulatory factor RBM3 is a proto-oncogene that prevents mitotic catastrophe. 1842 44

Cytokines produced in the tumour microenvironment have an important role in cancer pathogenesis. Altered cytokine expression may result in increased susceptibility to and/or poor prognosis in certain cancers. Therefore, the aim of this study was to investigate the influence of interleukin (IL)-8 and IL-10 on sporadic colon cancer development and progression. In our study, a statistically significant increase in IL-8 messenger RNA (mRNA) expression and decrease in IL-10 mRNA expression in tumour tissue compared with normal mucous tissue was observed (P = 0.003; P = 1.3 x 10(-9)). No association was found between IL-8 -251 A/T genotypes and IL-8 mRNA expression in tumour and corresponding normal mucous tissue, as well as susceptibility to sporadic colon cancer. Positive immunohistochemical IL-8 staining was more frequent in moderately and poorly differentiated tumours compared with well-differentiated tumours (P = 0.024). Finally, IL-8 significantly stimulated invasion of HT-29 cells in vitro (P = 0.000172). Significant association of IL-10 -1082 A/G, -819 T/C and -592 A/C genotypes and IL-10 mRNA expression in tumour tissue was observed (P = 0.022; P = 0.013; P = 0.02). Significant association of -819 T/C and -592 A/C genotypes and IL-10 mRNA expression in corresponding normal mucous tissue was observed (P = 0.01; P = 0.04) as well. IL-10 single-nucleotide polymorphism (SNP) promoter genotypes associated with low IL-10 mRNA expression (-819 TT; -592 AA) were also associated with increased risk of sporadic colon cancer compared with high-expression genotypes [odds ratio, 5.53; 95% confidence interval (CI), 1.53-20.1; odds ratio, 4.07; 95% CI, 1.28-12.96]. Positive IL-10 immunohistochemical reaction was more frequent in well-differentiated and moderately differentiated tumours compared with poorly differentiated tumours (P = 0.036). In Dukes' C tumours, positive IL-10 immunohistochemical reaction was less frequent compared with Dukes' A and B tumours (P = 0.023). Taken together, our results point to possible tumour promoting role of IL-8 and potential protective role of IL-10 in sporadic colon cancer.
 ...
PMID:Influence of interleukin-8 and interleukin-10 on sporadic colon cancer development and progression. 1862 51

Tissue factor (TF) is believed to play an important role in tissue repair, inflammation, angiogenesis, and tumor metastasis. Protease-activated receptors (PARs) are widely expressed on various cells including tumor cells and associated with many pathological mechanisms. In the present study, the expression of TF and PAR1, PAR2 on human colon cancer cells (SW620 and SW480) was investigated and their functional roles on the behavior of tumor cells were evaluated. It was demonstrated that SW620 and SW480 cells expressed TF at antigen, activity and mRNA levels. However, the highly metastatic cell line SW620 showed slightly higher TF expression than the low metastatic cell line SW480. The PAR2 antigen was strongly expressed on the membrane of SW620 cells, but not on SW480 cells. The PAR1 antigen was not observed in SW620 or SW480 cells, while PAR1 and PAR2 mRNA was detected in SW620 and SW480 cells. The migratory potential of SW620 was stronger than that of SW480 seen in Boyden chambers. PAR2 agonist (SLIGKV-NH2) and factor VIIa significantly stimulated SW620 cell proliferation, migratory activity, and interleukin 8 (IL-8) secretion compared to control. The stimulating effects of factor VIIa could be inhibited by anti-TF and anti-PAR2 but not anti-PAR1 antibodies. In summary, this study demonstrates that TF and PAR2 are strongly expressed on highly metastatic colonic tumor cells and are closely associated with the proliferation and migration of the cells. TF may elucidate its roles in colonic cancer invasion and metastasis via PAR2 pathway.
 ...
PMID:The expression and the functional roles of tissue factor and protease-activated receptor-2 on SW620 cells. 1894 3

We have shown that ObRb, the leptin receptor, is overexpressed in colorectal cancer cells, and that this may influence the patients' outcome. We investigated colonocytes as leptin targets and characterized their pivotal role in antitumor immune response. Cytokine and chemokine mRNAs in HT29 cells were measured by targeted arrays. In vitro, normal colonocytes and human colon cancer cells (HT29, Caco-2, SW480, and HCT116) were used to investigate ObRb transduction system and cytokine releases. Animal colonocytes and CD8 splenocytes and human HT29, HCT116, and CD8(+) cells from blood donors were used to investigate the lymphocyte response to the colonocytes when stimulated by leptin. Leptin-induced cytokine releases in the normal colonic mucosa and tumor growth and cytokine releases within tumors in vivo were measured in male rats and nude mice, respectively. Statistical analysis was done by Fisher's exact and Mann-Whitney U tests. Various cytokines and their receptors were produced in normal and tumoral colonocytes in response to leptin by increasing nuclear factor-kappaB activation. Interleukin-8 (IL-8) was the main cytokine produced in vitro. The levels of IL-8 and its receptor, CXCR1, were higher in tumors than in homologous normal mucosa. Systemic leptin enhanced the proinflammatory cytokines in normal colonocytes and in HT29 xenografted tumor colonocytes. Colonocyte-derived products after leptin treatment stimulated perforin and granzyme B expressions in normal CD8(+) T cells in vitro. Leptin triggers an inflammatory response in tumor tissue by directly stimulating colonocytes, which can recruit T cytotoxic cells in the tumor microenvironment.
 ...
PMID:Leptin receptor-related immune response in colorectal tumors: the role of colonocytes and interleukin-8. 1901 Sep 17

Colostrum, a nutrient-rich fluid produced by female mammals immediately after giving birth, is loaded with several immune, growth, and tissue repair factors. However, it remains unknown whether bovine colostrum has anti-inflammatory effects on intestinal epithelial cells (IEC). In this study, we aimed to investigate the anti-inflammatory effects of colostrum on IEC and to elucidate its molecular mechanisms. Human colon cancer HT-29 cells were stimulated with interleukin (IL)-1beta with or without bovine colostrum. The effects of colostrum on nuclear factor kappaB (NF-kappaB) signaling in HT-29 cells were examined using real-time reverse transcriptase-polymerase chain reaction detect IL-8 and intracellar adhesion molecule-1 mRNA expression using a NF-kappaB-dependent reporter gene assay and an electrophoretic mobility shift assay. Furthermore, we assessed the expression levels of inhibitor protein of NF-kappaB-alpha, cyclooxygenase-2, and p65 proteins by Western blotting. Bovine colostrum significantly inhibited IL-1beta-induced IL-8 and intracellar adhesion molecule-1 mRNA expression. Moreover, it suppressed IL-1beta-induced NF-kappaB activation, including NF-kappaB dependent reporter gene expression in a dose-dependent manner. Finally, Western blotting revealed that colostrum decreased the cyclooxygenase-2 protein expression level, inhibited inhibitor protein of NF-kappaB-alpha degradation, and blocked translocation of p65 into the nucleus. These data demonstrated that bovine colostrum might protect against IEC inflammation by inhibiting the NF-kappaB pathway, suggesting colostrum has a therapeutic potential for intestinal inflammation.
 ...
PMID:Bovine colostrum inhibits nuclear factor kappaB-mediated proinflammatory cytokine expression in intestinal epithelial cells. 1941 Sep 80

TNF-alpha is a major cytokine involved in inflammatory bowel disease (IBD). In this study, water extract of Grifola frondosa (GFW) was evaluated for its protective effects against colon inflammation through the modulation of TNF-alpha action. In coculture of HT-29 human colon cancer cells with U937 human monocytic cells, TNF-alpha-induced monocyte adhesion to HT-29 cells was significantly suppressed by GFW (10, 50, 100 micg/ml). The reduced adhesion by GFW correlated with the suppressed expression of MCP-1 and IL-8, the major IBD-associated chemokines. In addition, treatment with GFW significantly suppressed TNF-alpha-induced reactive oxygen species production and NF-kappaB transcriptional activity in HT-29 cells. In differentiated U937 monocytic cells, LPS-induced TNF-alpha production, which is known to be mediated through NF-kappaB activation, was significantly suppressed by GFW. In an in vivo rat model of IBD, oral administration of GFW for 5 days (1 g/kg per day) significantly inhibited the trinitrobenzene sulfonic acid (TNBS)-induced weight loss, colon ulceration, myeloperoxidase activity, and TNF-alpha expression in the colon tissue. Moreover, the effect of GFW was similar to that of intra-peritoneal injection of 5-aminosalicylic acid (5-ASA), an active metabolite of sulfasalazine, commonly used drug for the treatment of IBD. The results suggest that GFW ameliorates colon inflammation by suppressing production of TNF-alpha as well as its signaling through NF-kappaB leading to the expression of inflammatory chemokines, MCP-1 and IL-8. Taken together, the results strongly suggest GFW is a valuable medicinal food for IBD treatment, and thus may be used as an alternative medicine for IBD.
 ...
PMID:Grifola frondosa water extract alleviates intestinal inflammation by suppressing TNF-alpha production and its signaling. 2005 32


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>