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)

Neuropilins are membrane proteins that mediate effects on tumor cells directly and indirectly by affecting angiogenesis. Recent findings indicate that neuropilin 1 (NRP1) and the associated tyrosine kinase vascular endothelial growth factor receptor 2 (VEGFR2) play a regulatory role in developmental angiogenesis as well as in tumor angiogenesis. NRP1 and VEGFR2 might play a role in colon carcinogenesis and development of metastases. The significance of NRP1 expression in colon cancer seems to be controversial. Therefore, we aimed to distinguish between different expression patterns of signalling cascades in human colon carcinoma cell lines in order to analyze the role of NRP1 in tumorigenesis. We analyzed the biological significance of NRP1 in respect to VEGFR, EGFR, neuropilin and their ligands by RT-PCR and western blot with functional knock-out of NRP1 in different colon adenocarcinoma cell lines. There was no expression of VEGFR2 in tumor cell lines. There were cells that expressed: i) only NRP1 (HT-29, LS174T), ii) NRP2 (Colo320) or iii) both (SW480, LoVo). Cells without NRP1 expression strongly expressed EGFR but only when NRP2 was co-expressed. Inhibition of NRP1 expression by RNA interference did not alter growth characteristics in soft agar experiments. Furthermore, there were no differences in intracellular signalling pathways (ERK1/2 or AKT) in NRP1 inhibited cells. In ex vivo transfer experiments animals with tumors from siRNA-NRP1 transfected cells showed no significant inhibition of tumor growth compared to siRNA control. In conclusion, our results question the role of NRP1 function in VEGFR2 negative colon adenocarcinoma cells. NRP1 seems to have no detectable effect on proliferation or migration nor does it induce any changes in intracellular signalling pathways without the expression of VEGFR2. According to our data, further studies are needed to analyze the therapeutic relevance of NRP1 inhibition in vivo.
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PMID:No functional and transductional significance of specific neuropilin 1 siRNA inhibition in colon carcinoma cell lines lacking VEGF receptor 2. 1936 Feb 89

A secondary bile acid, namely, deoxycholic acid (DCA), has been known to promote colon tumors; on the other hand, it also induces apoptosis in several human colon cancer cell lines. A hydrophobic primary bile acid, namely, chenodeoxycholic acid (CDCA), exhibits a similar property of apoptosis induction; DCA and CDCA also trigger some specific intracellular signal pathways in the human colon cancer cell line HCT116. In this article, we report that hydrophobic bile acids induce different cellular responses depending on their concentration, that is, a sublethal concentration of hydrophobic bile acids can suppress the apoptosis induced by a higher concentration of DCA. Pretreatment with DCA or CDCA at a concentration of < or = 200 microM for 8 h suppressed the apoptosis induced by 500 microM DCA in HCT116 cells. Under this condition, the association of caspase-9 and Apaf-1 and subsequent activation of caspase-9 were inhibited, but the release of cytochrome c from the mitochondria was not. At 200 microM, DCA and CDCA induced the phosphorylation of Akt and ERK1/2, although these phosphorylations do not appear to be indispensable for the cytoprotection. It is interpreted that prolonged exposure to sublethal concentrations of hydrophobic bile acids induces resistance to apoptosis, leading to promotion of colorectal tumorigenesis.
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PMID:Biphasic regulation of cell death and survival by hydrophobic bile acids in HCT116 cells. 1937 11

The growth-inhibitory effects of the astaxanthin-rich Haematococcus pluvialis were studied in HCT-116 colon cancer cells. H. pluvialis extract (5-25 microg/ml) inhibited cell growth in a dose- and time-dependent manner, by arresting cell cycle progression and by promoting apoptosis. At 25 microg/ml of H. pluvialis extract, an increase of p53, p21(WAF-1/CIP-1) and p27 expression (220%, 160%, 250%, respectively) was observed, concomitantly with a decrease of cyclin D1 expression (58%) and AKT phosphorylation (21%). Moreover, the extract, at the same concentration, strongly up-regulated apoptosis by modifying the ratio of Bax/Bcl-2 and Bcl-XL, and increased the phosphorylation of p38, JNK, and ERK1/2 by 160%, 242%, 280%, respectively. Growth-inhibitory effects by H. pluvialis were also observed in HT-29, LS-174, WiDr, SW-480 cells. This study suggests that H. pluvialis may protect from colon cancer.
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PMID:Growth-inhibitory effects of the astaxanthin-rich alga Haematococcus pluvialis in human colon cancer cells. 1942 15

Erbin is an ErbB2 binding protein, which belongs to the LAP (leucine-rich repeat (LRR) and PDZ domain) protein family. We previously reported that Tax1, a protein of the human T-cell leukemia virus type I (HTLV-I), associated with Erbin by using Erbin PDZ domain as a bait to screen a human T lymphocyte cDNA library by a yeast two hybrid strategy. In the present study, we demonstrated that Tax1 enhances cancer cell proliferation via Ras-Raf-MEK-ERK signaling pathway by using molecular section strategy. The pull-down assay showed that the four amino acid domain, that is, Tax1 350-353, might specifically interact with Erbin, but not any other Tax1 deletion mutants. The coimmunoprecipitation assay confirmed that Tax1 350-353 domain bound with Erbin in vivo. Functional study demonstrated that overexpression of Tax1 in cancer cell lines of liver cancer SMMC-7721, colon cancer HCT-116, and breast cancer MCF-7 facilitated the cell proliferation. And the transfection of Tax1 353 in MCF-7 cells with endogenous Erbin expression markedly increased phosphorylation of Ras, Raf, MEK1/2, ERK1/2, PI3K, and IkappaBalpha, suggesting that Tax1-enhanced cell proliferation tracks Ras-Raf-MEK-ERK signaling pathway.
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PMID:Tax1 enhances cancer cell proliferation via Ras-Raf-MEK-ERK signaling pathway. 1947 91

Tetrandrine, a bisbenzylisoquinoline alkaloid, exerts antitumor effects against some cancers. We explored tetrandrine's effects on colon cancer with cultured mouse CT-26 cells and with subcutaneous tumors. Tetrandrine induced apoptosis in concentration- and time-dependent manner. Tetrandrine increased expression of ERK 1/2 and p38 MAPK; inhibition of p38 MAPK reduced tetrandrine-induced apoptosis; inhibition of ERK1/2 did not. Tetrandrine had significant effects on tumors including slower growth and longer animal survival time and higher survival rate. Higher dose and earlier treatment were more effective than lower dose and delayed treatment. TUNEL staining showed prominent tetrandrine-induced apoptosis of tumors. These data suggest that tetrandrine induced significant apoptosis of cultured and subcutaneous CT-26 cells. Tetrandrine-induced apoptosis might be at least partially related to activation of the p38 MAPK signaling pathway.
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PMID:Tetrandrine induces apoptosis and growth suppression of colon cancer cells in mice. 1958 12

Multiple lines of evidence have suggested a role for both bile acids and prostaglandins (PG) in gastrointestinal carcinogenesis. Levels of PGE(2) are determined by both synthesis and catabolism. Previously, bile acid-mediated induction of cyclooxygenase-2 (COX-2) was found to stimulate PGE(2) synthesis. NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the key enzyme responsible for the catabolism of PGE(2), has been linked to colorectal carcinogenesis. In this study, we determined whether bile acids altered the expression of 15-PGDH in human colon cancer cell lines. Treatment with unconjugated bile acids (chenodeoxycholate and deoxycholate) suppressed the transcription of 15-PGDH, resulting in reduced amounts of 15-PGDH mRNA, protein, and enzyme activity. Conjugated bile acids were less potent suppressors of 15-PGDH expression than unconjugated bile acids. Treatment with chenodeoxycholate activated protein kinase C (PKC), leading in turn to increased extracellular signal-regulated kinase (ERK) 1/2 activity. Small molecules that inhibited bile acid-mediated activation of PKC and ERK1/2 also blocked the downregulation of 15-PGDH. Bile acids induced early growth response factor-1 (Egr-1) and Snail, a repressive transcription factor that bound to the 15-PGDH promoter. Silencing Egr-1 or Snail blocked chenodeoxycholate-mediated downregulation of 15-PGDH. Together, these data indicate that bile acids activate the signal transduction pathway PKC --> ERK1/2 --> Egr-1 --> Snail and thereby suppress 15-PGDH transcription. Bile acids appear to increase the release of PGs from cells by downregulating catabolism in addition to stimulating synthesis. These results provide new mechanistic insights into the link between bile acids and gastrointestinal carcinogenesis.
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PMID:Bile acids inhibit NAD+-dependent 15-hydroxyprostaglandin dehydrogenase transcription in colonocytes. 1960 33

We studied the mechanism by which the para and meta positional isomers of nitric oxide-donating aspirin (NO-ASA) inhibit human colon cancer cell growth. These compounds are promising chemopreventive agents and represent a broader class of novel drugs. The two isomers differ drastically in their 24-h IC50s for cell growth, which are 12 microM for p-NO-ASA and 230 microM for m-NO-ASA. We examined their effects on cell signaling cascades, including predominantly the mitogen activated protein kinases (MAPKs). The principal differences between the two isomers were: a) p-NO-ASA exerts its effect earlier than m-NO-ASA; b) the predominant effect of m-NO-ASA is on ERK1/2 and Akt; whereas that of p-NO-ASA is on JNK1/2, while both activate p38, with p-NO-ASA showing a stronger and earlier effect; c) ATF-2 is more responsive to m-NO-ASA and c-Jun to p-NO-ASA; d) both isomers seem to have similar effects on AP-1 binding, the main difference between them being the timing of the effect; p-NO-ASA's effect is early and m-NO-ASA's is late; e) p-NO-ASA has an earlier and stronger effect on p21, while m-NO-ASA's effect occurs later and is weaker; and f) cell cycle changes follow the effect on p21 expression. Our findings underscore the role of positional isomerism in modulating the pharmacological effects of drugs and have potentially important implications for the further development of these chemoprevention agents.
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PMID:The differential cell signaling effects of two positional isomers of the anticancer NO-donating aspirin. 1972 20

Different proteins regulate iron metabolism at the level of various tissues. Among these is a second transferrin receptor (TfR2) that seems to play a key role in the regulation of iron homeostasis. Although TfR2 expression in normal tissues is restricted at the level of the liver, we observed that TfR2 is frequently expressed in cancer cell lines. Taking advantage of this observation we investigated TfR2 expression in primary colon cancers, and showed that this receptor is expressed in about 26% of cases. TfR2 expression in colon cancer is not related to histological grade, but is preferentially associated with mucinous tumors. In colon cancer cell lines, TfR2 is localized in membrane lipid rafts, induces ERK1/ERK2 phosphorylation, when activated by its ligand transferring, and is preferentially expressed during S-M phases of the cell cycle. The presence of TfR2 on the membrane of colon cancer cells may contribute the growth advantage to these cells.
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PMID:TfR2 expression in human colon carcinomas. 1972 24

CD10 expression is associated with metastases of colorectal cancer (CRC). In the present study, we examined association of CD10 with liver metastasis of CRC cells to clarify the therapeutic significance of CD10. CD10-positive human colon cancer cell line, HT29 cells showed inhibition of growth, invasion and colony formation by treatment with CD10 antisense S-oligodeoxynucleotide (S-ODN). In the mouse liver metastasis mode, CD10 antisense S-ODN-treated HT29 cells made less embedded cells in the liver than control HT29 cells. Number and size of metastatic foci in nude mice liver were reduced in CD10 antisense S-ODN-treated HT29 cells. Treatment with CD10 antisense S-ODN decreased phosphorylation of ERK1/2 and EGFR in HT29 cells. Intraperitoneal administration of liposome-capsulated CD10 antisense S-ODN inhibited establishment of liver metastasis and growth of established metastasis in nude mice. These findings suggest that CD10 is associated substantially with liver metastasis of CRC cells and might be a molecular target of CRC treatment.
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PMID:Antisense phosphorothioate oligodeoxynucleic acid for CD10 suppresses liver metastasis of colorectal cancer. 1981 87

Cruciferous vegetables contain isothiocyanates including diindolylmethane (DIM) that exhibit cancer chemopreventive effects. We developed a series of synthetic ring-substituted DIM analogs including 5,5'-dibromoDIM that exhibited better inhibitory activity in breast and colon cancer cells than DIM. In this study, we investigated whether 5,5'-dibromoDIM inhibits the proliferation of KB and YD-10B oral squamous carcinoma cell lines. 5,5'-dibromoDIM decreased the cell survival and inhibited the growth of oral cancer cells. Exposure of KB and YD-10B cells to 5,5'-dibromoDIM induced caspase-dependent apoptosis evidenced by poly-ADP ribose polymerase cleavage, accumulation of sub-G1 population, and nuclear condensation and fragmentation. In addition, apoptotic cell death was correlated with damage to the mitochondrial membrane potential through a decrease in the level of Bcl-2 protein expression. Mechanistic studies showed that mitochondria-dependent apoptosis induced by 5,5'-dibromoDIM was mediated by the p38 mitogen-activated protein kinase pathway but not the ERK1/2 and JNK pathway. These results highlight 5,5'-dibromoDIM as an important chemopreventive agent for the clinical treatment of oral cancer through the p38 mitogen-activated protein kinase pathway.
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PMID:The p38 MAPK pathway is critical for 5,5'-dibromodiindolylmethane-induced apoptosis to prevent oral squamous carcinoma cells. 1994 42


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