Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, delphinidin was found to suppress the phosphorylation of the epidermal growth factor receptor (EGFR) within human tumour cells (human colon carcinoma cell line (HT29), human vulva carcinoma cell line (A431)), albeit less effective than the flavonol quercetin. The higher potency of quercetin was also observed downstream on the level of the mitogen-activated protein kinase (MAPK) cascade. In addition, delphinidin, quercetin and (-)-epigallocatechin-3-gallate (EGCG) were found to suppress the phosphorylation of the ErbB2 receptor, with delphinidin exhibiting the strongest inhibitory properties. Their potency to suppress the ErbB2 receptor phosphorylation can be summarised as delphinidin > EGCG > quercetin. The effectiveness of delphinidin against the EGFR and the ErbB2 receptor was comparable, indicating a broader spectrum of activity against receptor tyrosine kinases. At low micromolar concentrations delphinidin showed some preference towards the ErbB2 receptor. In summary, quercetin and delphinidin appear to differ in their activity profile towards the ErbB receptor family members. Whereas quercetin was most effective against the EGFR, delphinidin exhibited some preference towards the ErbB2 receptor.
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PMID:Comparison of delphinidin, quercetin and (-)-epigallocatechin-3-gallate as inhibitors of the EGFR and the ErbB2 receptor phosphorylation. 1861 85

5-Fluorouracil (5-FU) is one of the most commonly used anticancer drugs in chemotherapy against various solid tumors. 5-FU dose-dependently increased the expression levels of intrinsic antiangiogenic factor thrombospondin-1 (TSP-1) in human colon carcinoma KM12C cells and human breast cancer MCF7 cells. We investigated the molecular basis for the induction of TSP-1 by 5-FU in KM12C cells. Promoter assays showed that the region with the Egr-1 binding site is critical for the induction of TSP-1 promoter activity by 5-FU. The binding of Egr-1 to the TSP-1 promoter was increased in KM12C cells treated with 5-FU. Immunofluorescence staining revealed that 5-FU significantly increased the level of Egr-1 in the nuclei of KM12C cells. The suppression of Egr-1 expression by small interfering RNA decreased the expression level of TSP-1. Furthermore, 5-FU induced the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and heat shock protein 27 (HSP27). Blockade of the p38 MAPK pathway by SB203580 remarkably inhibited the phosphorylation of HSP27 induced by 5-FU and decreased the induction of Egr-1 and TSP-1 by 5-FU in KM12C cells. These findings suggest that the p38 MAPK pathway plays a crucial role in the induction of Egr-1 by 5-FU and that induced Egr-1 augments TSP-1 promoter activity, with the subsequent production of TSP-1 mRNA and protein.
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PMID:Molecular basis for the induction of an angiogenesis inhibitor, thrombospondin-1, by 5-fluorouracil. 1875 17

The in vitro antitumor potential of novel pyrazino[1,2-b]-isoquinoline-4-ones that contain a half portion of significant natural products was explored in three cancer cell lines: MDA-MB 231 human breast carcinoma, A-549 human lung carcinoma, and HT-29 human colon carcinoma. In general, these compounds show mid to low muM GI(50)s, but LC(50)s over 100 microM with the exceptions of compounds 3b and 31 that are moderately toxic in all cell lines, while compound 4a is highly toxic and selective for HT-29 cells with LC(50) values in the high nanomolar range. Experiments directed to elucidate possible mechanisms of action with compounds 3a, 29, and 31 showed that compound 3a is able to efficiently induce apoptosis triggered directly from the G2/M phase of cell cycle, while compounds 29 and 31 are potentially cytostatic agents that induce the G1/S arrest of cell cycle. All three compounds do not act through DNA damage, since they do not activate this signaling at the level of sensors, transducers, and executers. Furthermore, the apoptosis induction of 3a is not mediated by activation of pro-apoptotic kinases JNK and p38 or by activation of AKT.
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PMID:Pyrazino[1,2-b]isoquinolines: synthesis and study of their cytostatic and cytotoxic properties. 1879 16

The apoptosis-inducing ability of hybrid compounds composed of macrosphelide and thiazole-containing side chain of epothilones was investigated. Among the tested series of hybrid compounds the one containing thiazole side chain at C15 (MSt-2) showed the maximum potency to induce apoptosis, while another containing thiazole side chain at C3 (MSt-6) was less potent. MSt-2 was found to induce apoptosis in human lymphoma (U937) cells in a dose- and time-dependent manner as confirmed by DNA fragmentation analysis. MSt-2 treated cells showed rapid reactive oxygen species (ROS) formation and c-Jun N-terminal kinase (JNK) activation. Furthermore, significant activation of extrinsic pathway as evident by Fas expression and caspase-8 activation was also observed. MSt-2-mediated decreased expression of Bid is an important event for cross talk between intrinsic and extrinsic signaling. N-acetyl-l-cysteine pre-treatment rescued cells from MSt-2-induced ROS formation, mitochondrial membrane potential (Delta psi(m)) loss, Fas expression, caspase-8 and -3 activation and DNA fragmentation. Moreover, antioxidant enzymes catalase and/or superoxide dismutase conjugated with polyethylene glycol also inhibit MSt-2-induced ROS formation, apoptosis and Delta psi(m) loss suggesting thereby pro-oxidant effects of MSt-2. Furthermore, JNK and pan-caspase inhibitors also protect cells from MSt-2-induced apoptosis. In addition to this, MSt-2 was found to be more potent in human colon carcinoma (HCT116) and human gastric cancer (AGS) cells while it has no effect on human normal dermal fibroblast. The important structure-activity relationship observed in the current study which makes MSt-2 more potent than MSt-6 is the position of thiazole side chain and stereochemistry of position 3 in chemical structure. In short the results of our study demonstrate that MSt-2-induced rapid ROS generation and mitochondrial dysfunction in cells trigger events responsible for mitochondria-dependent apoptosis pathway.
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PMID:Mechanism of apoptosis induced by a newly synthesized derivative of macrosphelides with a thiazole side chain. 1901 19

We investigated the expression of muscarinic acetylcholine receptors (mAChRs) and their possible involvement in the regulation of cell proliferation in four colon cancer cell lines (SNU-61, SNU-81, SNU-407, and SNU-1033) derived from Korean colon carcinoma patients. A ligand binding assay showed that all four cell lines expressed mAChRs. Treatment of the four cell lines with the cholinergic agonist carbachol led to the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2). In SNU-407 cells, carbachol significantly stimulated cell proliferation, which could be abolished by the muscarinic antagonist atropine and the ERK1/2 kinase inhibitor PD98059. These results indicate that mAChRs specifically mediate the proliferation of SNU-407 colon cancer cells via the ERK1/2 pathway.
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PMID:Enhanced proliferation of SNU-407 human colon cancer cells by muscarinic acetylcholine receptors. 1901 93

Loss of E-cadherin-mediated cell-cell contacts can elicit a signaling pathway that leads to acquisition of an invasive phenotype. Here, we show that at the receiving end of this pathway is the proto-oncogene c-Jun, a member of the activator protein-1 family of transcription factors that play a key role in stimulation of cell proliferation and tumor promotion. Cell separation or abrogation of E-cadherin-mediated cell-cell contacts both cause a dramatic increase in accumulation of the c-Jun protein. Unlike growth factors that enhance the expression of c-Jun by activating the transcription of the c-jun gene, the cell contact-dependent increase in c-Jun accumulation is not accompanied by a corresponding increase in c-Jun mRNA or c-Jun protein stability but rather in the translatability of the c-Jun transcript. Consistently, the increase in c-Jun accumulation is not dependent on activation of the mitogen-activated protein kinase or beta-catenin pathways but is mediated by signals triggered by the restructured cytoskeleton. Depolymerization of the cytoskeleton can mimic the effect of cell separation and cause a dramatic increase in c-Jun accumulation, whereas Taxol inhibits the cell contact-dependent increase. This novel mechanism of c-Jun regulation seems to underlie the robust overexpression of c-Jun in tumor cells of patients with colon carcinoma.
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PMID:Loss of E-cadherin-mediated cell-cell contacts activates a novel mechanism for up-regulation of the proto-oncogene c-Jun. 1919 63

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

Despite the reported cytotoxicity and apoptosis-inducing properties of sulforaphane (SF) in colon cancer cells, the details concerning individual mechanisms and signaling cascades underlying SF-mediated apoptosis remain unclear. To understand different aspects of SF-induced proapoptic signaling in advanced colon carcinoma, we investigated its mechanisms in metastatic SW620 cell line. Our results indicate that in SW620 cells SF acts to induce multivariate cascades including DNA-damage response pathway whose proapoptotic signaling is nevertheless reduced owing to the mutant status of p53 and caspase-2-JNK pathway which seems to complement and enhance p53-dependent signaling, however only in wild-type p53. Furthermore, both pathways require the active role of mitochondria and do not depend on generation of ROS, making SF an attractive chemopreventive agent whose antitumor properties should be further investigated in colon cancer.
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PMID:Activation of several concurrent proapoptic pathways by sulforaphane in human colon cancer cells SW620. 1956 59

The antitumor activity of fucoidan from Fucus vesiculosus was investigated in human colon carcinoma cells. The crude fucoidan, a polysaccharide composed predominantly of sulfated fucose, markedly inhibited the growth of HCT-15 cells (human colon carcinoma cells). After HCT-15 cells were treated with fucoidan, several apoptotic events such as DNA fragmentation, chromatin condensation and increase of the population of sub-G1 hypodiploid cells were observed. In the mechanism of fucoidan-induced apoptosis, we examined changes in Bcl-2 and Bax protein expression levels and activation of caspases. Fucoidan decreased Bcl-2 expression, whereas the expression of Bax was increased in a time-dependent manner compared to the control. In addition, the active forms of caspase-9 and caspase-3 were increased, and the cleavage of poly(ADP-ribose) polymerase (PARP), a vital substrate of effector caspase, was observed. Furthermore, the induction of apoptosis was also accompanied by a strong activation of extracellular signal-regulated kinase (ERK) and p38 kinase and an inactivation of phosphatidylinositol 3-kinase (PI3K)/Akt in a time-dependent manner. These findings provide evidence demonstrating that the pro-apoptotic effect of fucoidan is mediated through the activation of ERK, p38 and the blocking of the PI3K/Akt signal pathway in HCT-15 cells. These data support the hypothesis that fucoidan may have potential in colon cancer treatment.
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PMID:Apoptosis inducing activity of fucoidan in HCT-15 colon carcinoma cells. 1980 40

Epidemiological studies have shown that nutrition is a key factor in modulating sporadic colorectal carcinoma (CRC) risk. Aromatic plants of the genus Salvia (sage) have been attributed many medicinal properties, which include anticancer activity. In the present study, the antiproliferative and proapoptotic effects of water extracts of Salvia fruticosa (SF) and Salvia officinalis (SO) and of their main phenolic compound rosmarinic acid (RA) were evaluated in two human colon carcinoma-derived cell lines, HCT15 and CO115, which have different mutations in the MAPK/ERK and PI3K/Akt signalling pathways. These pathways are commonly altered in CRC, leading to increased proliferation and inhibition of apoptosis. Our results show that SF, SO, and RA induce apoptosis in both cell lines, whereas cell proliferation was inhibited by the two sage extracts only in HCT15. SO, SF, and RA inhibited ERK phosphorylation in HCT15 and had no effects on Akt phosphorylation in CO115 cells. The activity of sage extracts seems to be due, at least in part, to the inhibition of MAPK/ERK pathway.
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PMID:Salvia fruticosa, Salvia officinalis, and rosmarinic acid induce apoptosis and inhibit proliferation of human colorectal cell lines: the role in MAPK/ERK pathway. 1983 29


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