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)

Sphingolipid metabolites such as sphingosine-1-phosphate (S1P) and ceramide modulate apoptosis during development and in response to stress. In general, ceramide promotes apoptosis, whereas S1P stimulates cell proliferation and protects against apoptosis. S1P is irreversibly degraded by the enzyme S1P lyase (SPL). In this study, we show a crucial role for SPL in mediating cellular responses to stress. SPL expression in HEK293 cells potentiated apoptosis in response to stressful stimuli including DNA damage. This effect seemed to be independent of ceramide generation but required SPL enzymatic activity and the actions of p38 MAP kinase, p53, p53-inducible death domain protein (PIDD), and caspase-2 as shown by molecular and chemical inhibition of each of these targets. Further, SPL expression led to constitutive activation of p38. Endogenous SPL expression was induced by DNA damage in WT cells, whereas SPL knockdown diminished apoptotic responses. Importantly, SPL expression was significantly down-regulated in human colon cancer tissues in comparison with normal adjacent tissues, as determined by quantitative real-time PCR (Q-PCR) and immunohistochemical analysis. Down-regulation of S1P phosphatases was also observed, suggesting that colon cancer cells manifest a block in S1P catabolism. In addition, SPL expression and activity were down-regulated in adenomatous lesions of the Min mouse model of intestinal tumorigenesis. Taken together, these results indicate that endogenous SPL may play a physiological role in stress-induced apoptosis and provide an example of altered SPL expression in a human tumor. Our findings suggest that genetic or epigenetic changes affecting intestinal S1P metabolism may correlate with and potentially contribute to carcinogenesis.
 ...
PMID:Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer. 1709 Jun 86

Sphingolipids are an evolutionary conserved class of membrane lipids synthesized by all eukaryotic cells. The biological functions of sphingolipids are diverse, encompassing structural roles through their participation in membrane lipid rafts, and informational roles via the involvement of their metabolites in signal transduction pathways. An important sphingolipid metabolite is sphingosine-1-phosphate (S1P), which acts through G protein-coupled receptors present on mammalian cells, thereby stimulating cell proliferation, angiogenesis and inhibiting apoptosis. The main enzyme responsible for S1P synthesis, sphingosine kinase 1 (Sphk1), behaves as an oncogene in experimental systems and is required for polyp enlargement in the Min mouse model of intestinal tumorigenesis. S1P is irreversibly degraded by S1P lyase (SPL), an enzyme that is highly expressed in enterocytes, where it is involved in metabolism of dietary sphingolipids. Forced expression of SPL sensitizes human cells to various stressful stimuli and enhances apoptotic cell death. SPL expression is induced in response to DNA damaging agents in a time- and concentration-dependent manner. On the other hand, SPL is downregulated in human colon cancers and in Min mouse adenomas compared to adjacent uninvolved tissues. These observations suggest that SPL, like Sphk1, may play a role in tumorigenesis. Added support for this notion comes from the fact that S1P-specific antibodies slow tumor progression and angiogenesis in murine xenograft and allograft models. Together, these recent studies have established a link between S1P signaling, metabolism and carcinogenesis that may have implications regarding colon cancer screening, dietary chemoprevention and therapeutics.
 ...
PMID:Sphingosine-1-phosphate metabolism and intestinal tumorigenesis: lipid signaling strikes again. 1736 Oct 98

Dietary calcium (Ca) positively modulates the susceptibility to colon cancer, but its effects on related or earlier colonic pathologies, such as inflammation and mucosal dysregulation, are poorly understood. We tested the effects of differing dietary Ca levels on acute dextran sulfate sodium (DSS)-induced colitis in mice. BALB/c mice received a normal Ca (NCa) diet (0.5% Ca), a high Ca (HCa) diet (1.5% Ca), a low Ca (LCa) diet (0.05% Ca), or a very low Ca (VLCa) diet (0.009% Ca) for 3 wk. Mucosal caspases 1, 3, and 9 were assessed by Western blotting, and the histological crypt score was assessed by microscopy. Half of the mice in each group received DSS (1.5%) for 20 d in their drinking water, and disease activity was assessed. Increasing or lowering dietary Ca increased mucosal caspases (P < 0.0001 vs. NCa). Crypt scores increased with decreasing dietary Ca levels (P < 0.0001, r = -0.675), indicating that elevated caspases in LCa groups reflected early subclinical inflammation. DSS-induced disease activity was higher in mice fed low dietary Ca levels [P < 0.0001, VLCa and DSS vs. NCa and DSS (NCaDSS) and P < 0.005, LCa and DSS vs. NCaDSS], and mice from the VLCa group were moribund within 11 d of DSS administration. Those in the HCa group did not differ greatly from controls. Together, these data indicate that Ca protects against DSS-induced colitis in mice. The mechanisms are unclear, but the calcium-sensing receptor and/or luminal precipitates of calcium phosphate microparticles may be involved. Whether these observations can be extended to patients with colitis or infectious diarrhea deserves consideration.
 ...
PMID:Low dietary calcium levels modulate mucosal caspase expression and increase disease activity in mice with dextran sulfate sodium induced colitis. 1795 88

Sphingosine 1-phosphate (S1P), a lysophospholipid mediator that signals through G protein-coupled receptors, regulates a wide plethora of biological responses such as angiogenesis and immune cell trafficking. Detection and quantification of S1P in biological samples is challenging due to its unique physicochemical nature and occurrence in trace quantities. In this report, we describe a new method to selectively enrich S1P and dihydro-S1P from biological samples by the Fe(3+) gel immobilized metal affinity chromatography (IMAC). The eluted S1P from IMAC was dephosphorylated, derivatized with o-phthalaldehyde (OPA), and detected by high-performance liquid chromatography (HPLC) coupled to a fluorescence detector. IMAC purification of S1P was linear for a wide range of S1P concentration. Using this assay, secretion of endogenous S1P from endothelial cells, fibroblasts and colon cancer cells was demonstrated. We also show that dihydro-S1P was the major sphingoid base phosphate secreted from HUVEC over expressed with Sphk1 cDNA. Pharmcological antagonists of ABC transporters, glyburide and MK-571 attenuated endogenous S1P release. This assay was also used to demonstrate that plasma S1P levels were not altered in mice deficient for ABC transporters, Abca1, Abca7 and Abcc1/Mrp1. IMAC-based affinity-enrichment coupled with a HPLC-based separation and detection system is a rapid and sensitive method to accurately quantify S1P.
 ...
PMID:A novel method to quantify sphingosine 1-phosphate by immobilized metal affinity chromatography (IMAC). 1799 17

The goal of this study was to identify systematic alterations in key cell signaling and metabolic pathways that occur during colon cancer carcinogenesis and metastasis. Understanding gene expression changes in the context of specific pathways may increase our understanding of carcinogenesis and help guide treatment. Ten cases, with matched controls, were profiled for expression of >18,000 human transcripts using Affymetrix U133A chips. Data were filtered using GeneSifter. Gene expression levels for primary colon samples were compared to a normal colon while metastatic tissues were compared to the primary colon. Differentially regulated genes were associated using the Kyoto encyclopedia of genes and genome pathways to identify cell signaling and metabolic pathways altered during carcinogenesis and metastasis. Primary colon samples displayed high positive z-scores (indicating a gene ontology term that occurs more frequently than expected) for genes involved in Wnt-signaling (4.11), nitrogen metabolism (7.30) and inositol phosphate metabolism (2.47). Expression level changes for individual genes in each cluster were statistically significant (e.g. p=0.017 for cyclin D1 in the Wnt-signaling cluster). Metastatic tissue from the liver and omentum, but not the lung, displayed a decreased expression of genes important for oxidative phosphorylation. The metastatic tissue from all sites displayed a substantially decreased expression for genes involved in butanoate and propanoate metabolism and valine, leucine and isoleucine degradation. Our results demonstrate that systematic changes in gene expression occur for proteins involved in key cell signaling and metabolic pathways during the course of carcinogenesis and metastasis. These expression level changes complement the spectrum of mutations that characterize the progression of colorectal cancer.
 ...
PMID:Tissue-dependent and -independent gene expression changes in metastatic colon cancer. 1809 2

Orexins acting at the G protein-coupled receptor (GPCR) OX1R have recently been shown to promote dramatic apoptosis in cancer cells. We report here that orexin-induced apoptosis is driven by an immunoreceptor tyrosine-based inhibitory motif (ITIM) (IIY(358)NFL) present in the OX1R. This effect is mediated by SHP-2 phosphatase recruitment via a mechanism that requires Gq protein but is independent of phospholipase C activation. This is based on the following observations: 1) mutation of Y(358) into F abolished orexin-induced tyrosine phosphorylation in ITIM, orexin-induced apoptosis, and uncoupled OX1R from Gq protein in transfected Chinese hamster ovary (CHO) cells; 2) orexin-induced apoptosis in CHO cells expressing recombinant OX1R and in colon cancer cells expressing the native receptor was abolished by treatment with the tyrosine phosphatase inhibitor PAO and by transfection with a dominant-negative mutant of SHP-2; 3) orexins were unable to promote apoptosis in fibroblast cells invalidated for the G alpha q subunit and transfected with OX1R cDNA, whereas they promoted apoptosis in cells equipped with G alpha q and OX1R; and 4) the phospholipase C inhibitor U-73122 blocked orexin-stimulated inositol phosphate formation, whereas it had no effect on orexin-induced apoptosis in CHO cells expressing OX1R. These data unravel a novel mechanism, whereby ITIM-expressing GPCRs may trigger apoptosis.
 ...
PMID:A hallmark of immunoreceptor, the tyrosine-based inhibitory motif ITIM, is present in the G protein-coupled receptor OX1R for orexins and drives apoptosis: a novel mechanism. 1819 12

The vitamin D hormone, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], binds with high affinity to the nuclear vitamin D receptor (VDR), which recruits its retinoid X receptor (RXR) heterodimeric partner to recognize vitamin D responsive elements (VDREs) in target genes. 1,25(OH)(2)D(3) is known primarily as a regulator of calcium, but it also controls phosphate (re)absorption at the intestine and kidney. Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced in osteoblasts that, like PTH, lowers serum phosphate by inhibiting renal reabsorption through Npt2a/Npt2c. Real-time PCR and reporter gene transfection assays were used to probe VDR-mediated transcriptional control by 1,25(OH)(2)D(3). Reporter gene and mammalian two-hybrid transfections, plus competitive receptor binding assays, were used to discover novel VDR ligands. 1,25(OH)(2)D(3) induces FGF23 78-fold in osteoblasts, and because FGF23 in turn represses 1,25(OH)(2)D(3) synthesis, a reciprocal relationship is established, with FGF23 indirectly curtailing 1,25(OH)(2)D(3)-mediated intestinal absorption and counterbalancing renal reabsorption of phosphate, thereby reversing hyperphosphatemia and preventing ectopic calcification. Therefore, a 1,25(OH)(2)D(3)-FGF23 axis regulating phosphate is comparable in importance to the 1,25(OH)(2)D(3)-PTH axis that regulates calcium. 1,25(OH)(2)D(3) also elicits regulation of LRP5, Runx2, PHEX, TRPV6, and Npt2c, all anabolic toward bone, and RANKL, which is catabolic. Regulation of mouse RANKL by 1,25(OH)(2)D(3) supports a cloverleaf model, whereby VDR-RXR heterodimers bound to multiple VDREs are juxtapositioned through chromatin looping to form a supercomplex, potentially allowing simultaneous interactions with multiple co-modulators and chromatin remodeling enzymes. VDR also selectively binds certain omega3/omega6 polyunsaturated fatty acids (PUFAs) with low affinity, leading to transcriptionally active VDR-RXR complexes. Moreover, the turmeric-derived polyphenol, curcumin, activates transcription of a VDRE reporter construct in human colon cancer cells. Activation of VDR by PUFAs and curcumin may elicit unique, 1,25(OH)(2)D(3)-independent signaling pathways to orchestrate the bioeffects of these lipids in intestine, bone, skin/hair follicle, and other VDR-containing tissues.
 ...
PMID:Vitamin D receptor: key roles in bone mineral pathophysiology, molecular mechanism of action, and novel nutritional ligands. 1829 Jul 15

The phosphatidylinositol 3-kinase/AKT pathway is activated frequently in human cancer, and it has been implicated in tumor cell proliferation, survival, and chemoresistance. In this study, we addressed the role of AKT in cellular responses to the therapeutic methylating agent temozolomide (TMZ), and we investigated the possible link between TMZ-induced modulation of AKT function and activation of ataxia-telangiectasia and Rad3-related (ATR)- and ataxia telangiectasia mutated (ATM)-dependent signaling pathways. We found that clinically relevant concentrations of TMZ caused activation of endogenous AKT in lymphoblastoid cells, and in colon and breast cancer cells, and that this molecular event required a functional mismatch repair system. Transfection of a dominant-negative kinase-dead form of AKT1 into breast cancer cells abrogated TMZ-induced activation of endogenous AKT, and it markedly enhanced cell sensitivity to the drug. Likewise, exposure of the MMR-proficient cell lines to the AKT inhibitor D-3-deoxy-2-O-methyl-myo inositol 1-[(R)-2-methoxy-3-(octadecyloxy)-propyl hydrogen phosphate] (SH-5) impaired AKT phosphorylation in response to TMZ, and it significantly increased cell chemosensitivity. Furthermore, small interfering RNA (siRNA)-mediated reduction of AKT1 expression in colon cancer cells potentiated the growth inhibitory effects of TMZ. Inhibition of ATM expression in colon cancer cells by siRNA did not impair TMZ-induced activation of AKT, whereas siRNA-mediated inhibition of ATR prevented AKT activation in response to the drug and increased cell chemosensitivity. These results strongly support the hypothesis that clinical benefit could be obtained by combining TMZ with inhibitors of the AKT pathway. Moreover, they provide the first evidence of a novel function of ATR as an upstream activator of AKT in response to DNA damage induced by O(6)-guanine-methylating agents.
 ...
PMID:AKT is activated in an ataxia-telangiectasia and Rad3-related-dependent manner in response to temozolomide and confers protection against drug-induced cell growth inhibition. 1841 65

FTY720 (fingolimod), a novel immunosuppressant, was found to become biologically activated by phosphorylation into FTY720-1-phosphate (FTY720-P), which is a high-affinity agonist for sphingosine-1-phosphate (sphingosine-1-P)-receptors. FTY720 has also been reported to have a strong antitumor activity. The association between the phosphorylation of FTY720 and the growth inhibition of FTY720 against cancer cells are still not completely understood. In this study, we investigated the effects of FTY720, sphingosine, and their related compounds on the proliferation of human breast cancer cell lines (MCF-7, MDA-MB-231 and Sk-Br-3) and human colon cancer cell lines (HCT-116 and SW620). Non-phosphorylated FTY720, sphingosine and an FTY720 derivative, ISP-I-55, showed significant growth inhibition against these cells, with IC50 values of 5-20 microM at 48 h post-drug treatment. We confirmed that FTY720 induces the activation of a major mitogen-activated protein kinase, JNK, without the activation of p38 and down-regulation of phospho-ERK in MCF-7 breast cancer cells. In contrast, the phosphorylated derivatives, FTY720-P and sphingosine-1-P, as well as a phosphinane FTY720 derivative, cFTY720-P, did not inhibit the growth of the cells in the concentration range of 5-50 microM, whereas FTY720-P and sphingosine-1-P slightly induced the growth of MCF-7 cells. Combining FTY720 with dimethylsphingosine, a sphingosine kinase inhibitor, augmented the inhibitory effect of FTY720. These results indicate that the antiproliferative activity of FTY720 does not result from its phosphorylation, either endogenous or exogenous.
 ...
PMID:Effects of phosphorylation of immunomodulatory agent FTY720 (fingolimod) on antiproliferative activity against breast and colon cancer cells. 1852 51

Colonoscopy constitutes the principal investigation for colo-rectal neoplasms due to its ability to detect and remove most of precancerous lesions; due to the ongoing or planned colon cancer screening programs in many European countries we should expect an enormous increase in colonoscopic demand over the next few years. Diagnostic accuracy and therapeutic safety of colonoscopy strictly depends upon the quality of bowel cleansing which is often perceived as the most unpleasant part of the procedure in individuals undergoing this examination. The ideal preparation for colonoscopy should reliably empty the colon from all faecal material allowing the optimal visualization of the entire colonic mucosa without causing great patient's discomfort nor significant shifts in fluids or electrolytes. Standard PEG solutions and sodium phosphate (NaP) compounds are the most frequently used preparations; both are accepted and relatively well tolerated by the majority of patients undergoing colonoscopy; however, NaP compounds should be avoided in elderly subjects as well as in those with congestive heart failure, renal and hepatic insufficiency or taking diuretics, ACE inhibitors or angiotensin receptor blockers, since they can induce severe electrolyte and/or fluid disturbances. Standard PEG solutions are often taken incompletely due to the low palatability and the high volume of liquids required which induce nausea and vomiting with negative consequences in terms of colon cleansing. Reduced volume and better palatability of PEG solutions, such as those obtained with the newest PEG formulations, as well as improved patient education concerning the importance of bowel cleansing could undoubtedly increase compliance with oral bowel preparations and promote adherence to colo-rectal cancer screening programs.
 ...
PMID:Bowel preparation before colonoscopy in the era of mass screening for colo-rectal cancer: a practical approach. 1867 11


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