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)

Population studies provide evidence that obesity and insulin resistance are associated not only with elevated serum insulin levels and reduced serum adiponectin levels but also with increased risk of aggressive prostate and colon cancer. We show here that adiponectin activates AMP-activated protein kinase (AMPK) in colon (HT-29) and prostate (PC-3) cancer cells. These results are consistent with prior observations in myocytes, but we show that in epithelial cancer cells AMPK activation is associated with reduction in mammalian target of rapamycin activation as estimated by Ser(2448) phosphorylation, with reduction in p70S6 kinase activation as estimated by Thr(389) phosphorylation, with ribosomal protein S6 activation as estimated by Ser(235/236) phosphorylation, with reduction in protein translation as estimated by [(35)S]methionine incorporation, and with growth inhibition. Adiponectin-induced growth inhibition is significantly attenuated when AMPK level is reduced using small interfering RNA, indicating that AMPK is involved in mediating the antiproliferative action of this adipokine. Thus, adiponectin has the characteristics of a AMPK-dependent growth inhibitor that is deficient in obesity, and this may contribute to the adverse effects of obesity on neoplastic disease. Furthermore, metformin was observed to activate AMPK and to have growth inhibitory actions on prostate and colon cancer cells, suggesting that this compound may be of particular value in attenuating the adverse effects of obesity on neoplasia.
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PMID:The effects of adiponectin and metformin on prostate and colon neoplasia involve activation of AMP-activated protein kinase. 1913 81

A series of ferrocenyl ester complexes, varying the lipophilic character of the pendant groups, was prepared and characterized by spectroscopic and analytical methods. The syntheses of Fe(C(5)H(4)CO(2)CH(3))(2), Fe(CpCOOCH(3)) (CpCOO CH(2)CH(3)), and Fe(CpCOOCH(2)CH(3))(2) are reported. The solid-state structure of Fe(C(5)H(4)CO(2)CH(3))(2) has been determined by X-ray crystallography. Fe(C(5)H(4)CO(2)CH(3))(2) has the cyclopentadienyl rings virtually in an eclipsed conformation with the pendant groups not completely opposite to each other. Cyclic voltammetry characterization showed that the functionalized ferrocenes oxidize at potentials, E(pa), higher than ferrocene as a result of the electro withdrawing effect of the pendant groups on the cyclopentadienyl ligand. The cytotoxicities of Fe(C(5)H(4)CO(2)CH(2)CH(2)OH)(2), Fe(C(5)H(4)CO(2)CH(2)CH=CH(2))(2), Fe(C(5)H(4)CO(2)CH(3))(2), Fe(CpCOOCH(3))(CpCOOCH(2)CH(3)), and Fe(CpCOOCH(2)CH(3))(2) in colon cancer HT-29 and breast cancer MCF-7 cell lines were measured by the MTT biological viability assay and compared to ferrocene and ferrocenium. Fe(C(5)H(4)CO(2)CH(2)CH=CH(2))(2) showed the best IC(50) values, 180(10) muM for HT-29 and 190(30) muM for MCF-7 cell lines, with cytotoxicities similar to ferrocenium. The cytotoxic data suggest that as we increase the lipophilic character of the functionalized ferrocene, the cytotoxicity improves approaching to the cytotoxic activity of ferrocenium.
Met Based Drugs 2009
PMID:Synthesis, structure, electrochemistry, and cytotoxic properties of ferrocenyl ester derivatives. 1932 25

Survival rates from colorectal cancer (CRC) differ dramatically according to the stage of the tumor at diagnosis, with survival rates of 90% for patients with stage I disease but only 49% for those with stage III cancer. Many serum and tumor markers have been identified but none has provided a significant improvement over tumor stage as a prognostic indicator for cancer recurrence for patients with stage II or III disease. Aberrant activation of the hepatocyte growth factor (HGF)/HGF receptor (MET) signaling pathway is associated with both malignant transformation and metastatic potential of CRC. MACC1 (metastasis-associated in colon cancer-1) is a newly discovered gene that regulates this signaling cascade. The significant correlation between overexpression of MACC1 in CRC and both malignant transformation and subsequent risk for metastases in stage II and III CRC indicates that MACC1 tumor typing may prove valuable for determining risk for CRC recurrence. MACC1 may also be an important therapeutic target for CRC treatment.
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PMID:Overexpression of MACC1 leads to downstream activation of HGF/MET and potentiates metastasis and recurrence of colorectal cancer. 1934 7

Colorectal cancer, one of the most challenging malignancies, still has a limited number of recognized prognostic and predictive markers indicating appropriate treatment. MACC1 (metastasis-associated in colon cancer-1), a novel regulator of tumor growth and metastasis has recently been identified as an important prognostic factor of metastatic disease in colorectal cancer. The mechanism of MACC1 activity remains undetermined. Here we apply a combination of fold recognition and homology modeling algorithms to draft MACC1 function. The applied methods revealed that the MACC1 protein consists of four domains: ZU5, SH3, and two C-terminal death domains (DD). Previously a similar domain architecture (ZU5-DD) was observed in other proteins, involved mainly in signal transduction and apoptosis regulation. Based on the specific aspects of the closest homologues' biology functional hypotheses on MACC1 are proposed. A broad range of bioinformatic analyzes indicates that MACC1, besides its involvement in signal transduction from the MET receptor, links MET signaling and apoptosis.
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PMID:Unexpected domain composition of MACC1 links MET signaling and apoptosis. 1949 89

Protein homeostasis relies on a balance between protein synthesis and protein degradation. The ubiquitin-proteasome system is a major catabolic pathway for protein degradation. In this respect, proteasome inhibition has been used therapeutically for the treatment of cancer. Whether inhibition of protein degradation by proteasome inhibitor can repress protein translation via a negative feedback mechanism, however, is unknown. In this study, proteasome inhibitor MG-132 lowered the proliferation of colon cancer cells HT-29 and SW1116. In this connection, MG-132 reduced the phosphorylation of mammalian target of rapamycin (mTOR) at Ser2448 and Ser2481 and the phosphorylation of its downstream targets 4E-BP1 and p70/p85 S6 kinases. Further analysis revealed that MG-132 inhibited protein translation as evidenced by the reductions of (35)S-methionine incorporation and polysomes/80S ratio. Knockdown of raptor, a structural component of mTOR complex 1, mimicked the anti-proliferative effect of MG-132. To conclude, we demonstrate that the inhibition of protein degradation by proteasome inhibitor represses mTOR signaling and protein translation in colon cancer cells.
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PMID:Repression of protein translation and mTOR signaling by proteasome inhibitor in colon cancer cells. 1954 Jan 99

Colon cancer is still the second most frequent malignancy in the Western world. Despite major efforts in diagnosis and treatment it is one of the leading causes of cancer related deaths. The metastatic dissemination of primary tumors is directly linked to patient's survival and accounts for about 90% of all colon cancer deaths. Current clinical predictions on whether colon cancer will metastasize are mainly defined by histopathological staging, describing the tumor spread within a surgical specimen. This review focuses on the need for molecule-based staging as essential prerequisite for individualized diagnosis, prognosis and therapy. Molecular determinants for progression and metastasis of colon cancer are discussed. Moreover, a newly identified molecule playing a decisive role in colon cancer metastasis is highlighted: MACC1. MACC1 acts as a key regulator of the metastasis-inducing HGF/Met pathway, predicts the risk for metastasis in early cancer stages, and represents a novel target to attack metastasis.
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PMID:Colon cancer metastasis: MACC1 and Met as metastatic pacemakers. 1966 36

Colorectal cancer is the second leading cause of cancer-related deaths in the U.S. Met, the receptor for hepatocyte growth factor (HGF), is over-expressed in colon tumors and is associated with poor prognosis. Recently, the green tea polyphenol (-)-epigallocatechin gallate (EGCG) was reported to suppress Met activation in breast cancer cells. However, the possible confounding effect of hydrogen peroxide (H(2)O(2)), produced when EGCG is added to cell culture media, was not assessed. In the present study, the human colon cancer cell lines HCT116 and HT29 were used to examine the relationships between Met activation, EGCG treatment, and H(2)O(2) generation. At concentrations of 0.5, 1, and 5 microM, EGCG suppressed markedly the activation of Met in the presence of HGF. Concentrations of 10muM EGCG and below generated low amounts of H(2)O(2) (<1.5 microM), whereas higher H(2)O(2) concentrations (>5 microM) were required to directly increase the phosphorylation of Met. Moreover, suppression of Met activation by EGCG occurred in the presence or absence of catalase, suggesting that such effects were not an 'artifact' of H(2)O(2) generated from EGCG in cell culture media. We conclude that EGCG might be a beneficial therapeutic agent in the colon, inhibiting Met signaling and helping to attenuate tumor spread/metastasis, independent of H(2)O(2)-related mechanisms.
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PMID:Suppression of Met activation in human colon cancer cells treated with (-)-epigallocatechin-3-gallate: minor role of hydrogen peroxide. 1974 67

We recently identified the metastasis-associated in colon cancer 1 (MACC1) gene by a genome-wide search for differentially expressed genes in human colon cancer tissues, metastases, and normal tissues. Based on MACC1 expression in primary colon cancers, which did not present with metastases, our negative and positive prediction for metachronous metastasis was correct in 80% and 74% of cases, respectively. The 5-year-survival was 80% for MACC1 low expressors, but 15% for individuals who showed high MACC1 expression in their primary tumors. MACC1 induces migration, invasion and proliferation in cell culture, and liver and lung metastases in xenograft models. Here, we describe features of MACC1 beyond its utility as an indicator of metastasis. We elucidate its genomic localization and organization, its predicted splice variants, and single nucleotide polymorphisms. We discuss the MACC1 protein domain structure, posttranslational modifications, its conservation through evolution, and some family ties to SH3BP4. Furthermore, we summarize the predicted expressions of MACC1 in normal and malignant human tissues. We also evaluate the MACC1 levels in the context of one of its transcriptional targets, the receptor tyrosine kinase Met that activates the hepatocyte growth factor/Met signaling pathway, leading to enhanced cell motility, invasion, and metastasis.
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PMID:MACC1 - more than metastasis? Facts and predictions about a novel gene. 1978 27

Most cancer deaths result from spread of the primary tumor to distant sites (metastasis). MET is an important protein for metastasis in multiple tumor types. Here we report on the ability of tea catechins to suppress MET activation in human colon cancer cells and propose a mechanism by which they might compete for the kinase domain of the MET protein.
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PMID:Tea catechins inhibit hepatocyte growth factor receptor (MET kinase) activity in human colon cancer cells: kinetic and molecular docking studies. 1983 93

The Met receptor tyrosine kinase is deregulated in a variety of cancers and is correlated with advanced stage and poor prognosis. Thus, Met has been identified as an attractive candidate for targeted therapy. We compared the tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) and a specific Met inhibitor, SU11274, as suppressing agents of Met signaling in HCT116 human colon cancer cells. Treatment with hepatocyte growth factor increased phospho-Met levels, and this was inhibited in a concentration-dependent manner by EGCG and SU11274 (IC(50) 3.0 vs. 0.05muM, respectively). Downstream activation of Erk and Akt signaling pathways also was suppressed. Both compounds at a concentration of 5muM lowered cell viability and proliferation, with EGCG being more effective than SU11274, and the invasion of colon cancer cells in Matrigel assays was strongly inhibited. These findings are discussed in the context of the pleiotropic effects of tea catechins, their tissue metabolite levels, and the potential to inhibit colon cancer metastasis and invasion.
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PMID:(-)-Epigallocatechin-3-gallate inhibits Met signaling, proliferation, and invasiveness in human colon cancer cells. 2036 25


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