Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

S-Adenosylmethionine (SAMe) and its metabolite 5'-methylthioadenosine (MTA) inhibit mitogen-induced proliferative response in liver and colon cancer cells. SAMe and MTA are also proapoptotic in liver cancer cells by selectively inducing Bcl-x(S) expression. The aims of this work were to assess whether these agents are proapoptotic in colon cancer cells, and if so, to elucidate the molecular mechanisms. We found that both SAMe and MTA are proapoptotic in HT-29 and RKO cells in a dose- and time-dependent manner. Gene microarray uncovered down-regulation of cellular FLICE inhibitory protein (cFLIP). SAMe and MTA treatment led to a decrease in the mRNA and protein levels of both the long and short cFLIP isoforms. This required de novo RNA synthesis and was associated with activation of procaspase-8, Bid cleavage, and release of cytochrome c from the mitochondria. Inhibiting caspase 8 activity or overexpression of cFLIP protected against apoptosis, whereas supplementing with polyamines did not. SAMe and MTA treatment sensitized RKO cells to tumor necrosis factor alpha-related apoptosis-inducing ligand-induced apoptosis. Although SAMe and MTA are proapoptotic in colon cancer cells, they have no toxic effects in NCM460 cells, a normal colon epithelial cell line. In contrast to liver cancer cells, SAMe and MTA had no effect on Bcl-x(S) expression in colon cancer cells. In conclusion, SAMe and MTA are proapoptotic in colon cancer cells but not normal colon epithelial cells. One molecular mechanism identified is the inhibition of cFLIP expression. SAMe and MTA may be attractive agents in the chemoprevention and treatment of colon cancer.
Mol Pharmacol 2009 Jul
PMID:S-Adenosylmethionine and methylthioadenosine inhibit cellular FLICE inhibitory protein expression and induce apoptosis in colon cancer cells. 1937 10

Changes in N-linked glycosylation are known to occur during the development of cancer. For example, increased branching of oligosaccharides has been associated with metastasis and has been correlated to tumor progression in human cancers of the breast, colon, and melanomas. Increases in core fucosylation have also been associated with the development of hepatocellular carcinoma (HCC). To a large extent, the proteins to which these N-linked glycans are attached have been unknown. However, with the advent of sensitive glycan analysis and proteomic technologies, the ability to comprehensively identify all the fucosylated proteins in a given population is now a possibility. This method, generally referred to as targeted glycoproteomics, is shown as applied to the detection of proteins present in the fucosylated proteome of a liver cancer cell line but is generally enough to be applied in many other situations.
Methods Mol Biol 2009
PMID:Glycoproteomic analysis by two-dimensional electrophoresis. 1938 47

In the past 10 years, transcriptome and proteome analyses have provided valuable data on global gene expression and cell functional networks. However, when integrated,these analyses revealed partial correlations between mRNA expression levels and protein abundance thus suggesting that post-transcriptional regulations may be in part responsible for this discrepancy. In the present work, we report the development of a functional, integrated, and quantitative method to measure post-transcriptional regulations that we named FunREG. This method enables (i) quantitative measure of post-transcriptional regulations mediated by selected 3-untranslated regions and exogenous small interfering-RNA or micro-RNAs and (ii) comparison of these regulatory processes in physiologically relevant systems (e.g. cancer versus primary untransformed cells). We applied FunREG to the study of liver cancer, and we demonstrate for the first time the differential regulatory mechanisms controlling gene expression at a post-transcriptional level in normal and tumoral hepatic cells. As an example, translation efficiency mediated by heparin-binding epidermal growth factor 3-untranslated region was increased 3-fold in liver cancer cells compared with normal hepatocytes, whereas stability of an mRNA containing a portion of Cyclin D1 3-untranslated region was increased more than 2-fold in HepG2 cells compared with normal hepatocytes. Consequently we believe that the method presented herein may become an important tool in fundamental and medical research. This approach is convenient and easy to perform, accessible to any investigator, and should be adaptable to a large number of cell type, functional and chemical screens, as well as genome scale analyses. Finally FunREG may represent a helpful tool to reconcile transcriptome and proteome data.
Mol Cell Proteomics 2009 Aug
PMID:Analysis of post-transcriptional regulations by a functional, integrated, and quantitative method. 1941 Dec 82

The objective of this study was to identify genes regulated by thyroid hormone (T(3)) mediated by its receptor (TR) and associated with tumorigenesis. The gene encoding aldo-keto reductase family 1, member B1 (AKR1B1), as previously identified by c-DNA microarray, is known to be up-regulated by T(3) treatment. Enzyme AKR1B1 was elevated roughly 3-fold in HepG2-TRalpha1 cells at the protein level and 4.6-fold increase at the mRNA level after 48 h T(3) treatment. Similar findings were obtained from thyroidectomized rats after T(3) application. To identify and localize the critical TR element (TRE), series deletion of the promoter mutant were constructed and electrophoretic mobility shift assays were carried out. The TRE on the AKR1B1 promoter was localized to the -1099/-1028 region. Further, this study demonstrated that AKR1B1 over-expression in some types of hepatocellular carcinomas (HCCs) is TR-dependent and might play a crucial role in the development of HCC. Thus, T(3) regulates AKR1B1 gene expression via a TRE-dependant mechanism and associates liver cancer.
Mol Cell Endocrinol 2009 Aug 13
PMID:Regulation of AKR1B1 by thyroid hormone and its receptors. 1942 79

Malignant transformation of hepatocytes is frequently associated with upregulation of HLA-A expression. Currently there is no information available regarding the mechanisms underlying this phenotypic change. We investigated HLA-A expression in 165 paraffin embedded tissues and 21 fresh tissues from liver cancer patients. Utilizing truncated HLA-A promoter-reporter constructs and gel-shift assay we had identified the regulatory elements and transcription factors required for HLA-A upregulation. 54% of the paraffin embedded tissues showed increased HLA-A expression in their cancerous part. 43% of the fresh liver cancer tissues had increased HLA-A complex expression with the HLA-A heavy chain gene demonstrating the highest level of upregulation (62%). Enhanced HLA-A expression in the liver cell lines QGY7701 and BEL7402 was found to be mediated by binding of interferon regulatory factor 1 (IRF-1) to interferon stimulated response element, and of nuclear transcription factor p65 binding to enhancer A element in the HLA-A promoter of these cell lines. The in vivo relevance of these findings was indicated by the association of the enhanced expression of IRF-1 and accumulation of nuclear p65 with HLA-A upregulation in 8 of the 21 liver cancer lesions investigated. Our results indicated that HLA-A upregulation in liver cancer was mediated by both increased nuclear aggregation of transcription factor p65 and upregulation of transcription factor IRF-1.
Mol Immunol 2009 Jun
PMID:IRF-1 and p65 mediate upregulation of constitutive HLA-A antigen expression by hepatocellular carcinoma cells. 1942 10

There is indirect multiple evidence that hints at a potential role of sex steroids in development and progression of human hepatocellular carcinoma (HCC). In the present study, we have investigated androgen metabolism in a panel of human liver cancer cell lines (HA22T, Huh7, HepG2) and in normal, cirrhotic and malignant human liver tissues aiming to dissect the potential impact of individual enzyme activities and their products in normal and diseased human liver, both in vivo and in vitro. Using our intact cell analysis we were able to assess rates and pathways of androgen metabolism in living conditions. Overall, incubation of cultured cells or tissue minces with either testosterone (T) or androstenedione (Ad) used as precursor resulted in a large extent of 17betaoxidation of T to Ad (cells: 28-77%; tissues: 35-50%). In malignant liver cell lines, both HA22T and Huh7 cells showed consistent amounts of the 5alpha-reductase enzyme products (18% and 15%, respectively), while 5beta-reductase activity was more pronounced in Huh7 cells (18%) than in HA22T cells (1.8%). Interestingly, a significant extent of estrogen formation could be observed in Huh7 cells (5.4-11.5%), while no aromatase activity could be detected in HA22T cells. In HepG2 cells, along with a relatively high proportion of Ad, estrogens represented the most prominent (50-55%) end product of androgen metabolism, regardless of the precursor used. In liver tissues, equivalent results could be obtained, with a consistent proportion of 17betaoxidation of T to Ad (35-50%) being observed in the majority of samples. However, while normal liver tissue samples exhibited a minor proportion of bioactive androgens (3.4%) with no aromatase products, HCC tissues showed a significant extent of aromatase activity (nearly 20%) with estrogen representing the most prominent metabolic product after 24h incubation with either T or Ad. HCV and alcoholic cirrhotic tissues displayed different patterns of androgen metabolism. The former produced limited amounts of bioactive androgens (5.3%) and considerable levels of the intermediate aromatase product 19OH-Ad (up to 28%), the latter exhibited a prevalence of androgen degradation through the 5beta-reductase pathway (9.8%) and a significant extent of aromatase activity (16% as a whole). In conclusion, three major metabolic states could be depicted, depending on prevalent pathways of androgen metabolism and steroid receptor status: estrogenic, androgenic, and mixed. This model supports the idea that local estrogen biosynthesis may be implicated in human HCC and provides a basis for the exploitation of aromatase inhibitors and/or ER antagonists or selective estrogen receptor modulators (SERMs) as a new therapeutic strategy in HCC patients.
J Steroid Biochem Mol Biol 2009 Feb
PMID:Androgen metabolism and biotransformation in nontumoral and malignant human liver tissues and cells. 1942 35

Activation of the nuclear transcription factor-kappaB (NF-kappaB) has been implicated in liver tumorigenesis. We evaluated the effects of a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in two human liver cancer cell lines HA22T/VGH and HuH-6. DHMEQ treatment dose dependently decreased the DNA-binding capacity of the NF-kappaB p65 subunit, inhibited cell growth and proliferation, and increased apoptosis as shown by caspase activation, release of cytochrome c, poly(ADP-ribose) polymerase cleavage, and down-regulation of survivin. DHMEQ also induced a dose-dependent activation of mitogen-activated protein kinase kinase/extracellular signal-regulated kinase signaling, and inhibition of this pathway significantly reduced cell growth. It is noteworthy that we observed that DHMEQ stimulated reactive oxygen species (ROS) production in a dose-dependent manner and that pretreatment of the cells with the antioxidant N-acetyl-L-cysteine (NAC) significantly reduced DHMEQ-induced ROS generation. Accordingly, NAC completely reversed the DHMEQ-induced growth inhibition, caspase activation, and cell death. DHMEQ-treated cells exhibited DNA damage, as evaluated by accumulation in nuclear foci of phospho-H2AX, which was completely reversed by NAC. Moreover, DHMEQ induced the expression of genes involved in the endoplasmic reticulum stress response (GRP78, CHOP, TRB3) and promoted the splicing of XBP1 mRNA in a dose-dependent fashion in both cell lines, which was reversed in the presence of NAC. Knockdown of TRB3 mRNA expression by small interference RNA significantly decreased DHMEQ-induced cell growth inhibition. These data suggest that DHMEQ antitumor effects are primarily mediated through ROS generation. Thereby, considering that cancer cells are under increased ER stress and oxidative stress conditions, DHMEQ may greatly improve various anticancer strategies.
Mol Pharmacol 2009 Aug
PMID:Antitumor effects of dehydroxymethylepoxyquinomicin, a novel nuclear factor-kappaB inhibitor, in human liver cancer cells are mediated through a reactive oxygen species-dependent mechanism. 1946 Oct 54

The identification of a subpopulation of brain tumor cells with potent tumorigenic capacity strengthens the cancer stem cell hypothesis of the origin of the tumors that has recently attracted the attention of many researchers. Reports have been published on the identification of tumor cells with stem cells characteristics in different types of tumors (acute myelogenic leukemia, breast cancer, prostate cancer, bone sarcomas, liver cancer, and melanomas). We and other groups have previously reported the isolation of cancer stem cells from adult glioblastoma multiforme. These cells express stem cell markers, and when differentiated they express glial and neuronal markers. In vivo they give a tumor that recapitulates the characteristics of the tumor in the patient. More recently we have isolated tumor stem-like cells also from benign tumors like pituitary adenomas. Cells derived from pituitary adenomas are able to grow as floating aggregates resembling the neurospheres (typical of normal stem cells) in a medium supplemented by growth factors (EGF and bFGF). The immunocytochemical analysis revealed that pituitary tumor stem-like cells are positives for nestin and, when grown for ten days in differentiation medium they express GFAP, BIII tubulin, and S-100. In vitro tumor stem-like cells derived from a patient with a somatotroph adenoma showed high production of growth hormone and prolactin, while cells derived from the same patient but grown in presence of fetal bovine serum showed no production of hormones.
Methods Mol Biol 2009
PMID:Pituitary adenoma stem cells. 1958 28

Most cancers rely disproportionately on glycolysis for energy even in the presence of adequate oxygen supply, a condition known as "aerobic glycolysis", or the Warburg effect. Pharmacological reversal of the Warburg effect has been shown to cause selective apoptosis of tumor cells, presumably by stimulating mitochondrial respiratory chain activity and production of reactive oxygen species that, in turn, induce a caspase-mediated series of reactions leading to cell death. We reasoned that a similar effect on tumor cells might result from up-regulation of the E1alpha subunit gene (pda1) of the pyruvate dehydrogenase complex (PDC) that catalyzes the rate-limiting step in aerobic glucose oxidation and thus plays a major role in the control of oxidative phosphorylation. To test this postulate, we employed a self-complementary adeno-associated virus (scAAV)-based delivery and expression system for targeting pda1 to the mitochondria of primary cultures of human hepatoblastoma (HB) and hepatocellular carcinoma (HCC) cells. Serotypes 1-10 scAAV vectors that included enhanced green fluorescent (egfp) reporter gene driven by either cytomegalovirus (CMV) or chicken beta-actin (CBA) promoters were analyzed for transduction ability of HB (Huh-6) and HCC (Huh-7 and HepG2) cell lines and primary cultures of normal human hepatocytes. Serotype 3 scAAV-egfp (scAAV3-egfp) vector was the most efficient and transduced up to 90% of cells. We limited the transgene expression primarily to liver cancer cells by generating scAAV3 vectors that contained the human alpha-fetoprotein promoter (AFP)-driven reporter gene (scAAV3.AFP-egfp) and the potentially therapeutic gene scAAV3.AFP-pda1. Infection of Huh-6 cells by the scAAV3.AFP-pda1 vector increased protein expression of E1alpha, PDC catalytic activity, and late-stage apoptotic cell death. Apoptosis was also associated with increased protein expression of Bcl-X/S, an early marker of apoptosis, and release of cytochrome c into the cytosol of infected HB cells. These data indicate that molecular targeting of mitochondrial oxidative metabolism in liver cancer cells by AAV3-mediated delivery of pda1 holds promise as a novel and effective therapeutic approach for human hepatic tumors.
Mol Genet Metab 2009 Nov
PMID:AAV3-mediated transfer and expression of the pyruvate dehydrogenase E1 alpha subunit gene causes metabolic remodeling and apoptosis of human liver cancer cells. 1958 87

Liver cirrhosis and hepatocellular carcinoma (HCC) are fatal sequelaes of chronic hepatitis B in China. The sera from HCC and cirrhosis were profiled by rapid resolution liquid chromatography coupled with quadrupole time-of-flight (Q-TOF) mass spectrometry. Reversed-phased (RP) liquid chromatography and hydrophilic interaction chromatography (HILIC) were used for the data acquisition. The normalized and combined data were handled by chemometric analysis, and the combination proved to be effective and reliable for the orthogonal projection to latent structures (OPLS) analysis. Metabonomic profiles and the potential biomarkers were found based on the OPLS models. Shared and unique structure (SUS) plots were used for the evaluation of the potential biomarkers. Glycocholic acid, glycochenodeoxycholic acid, taurocholic acid and taurochenodesoxycholic acid were found to be potential biomarkers related to liver cirrhosis, while dihydrosphingosine and phytosphingosine were potential diagnostic biomarkers of HCC. The other identified metabolites were considered as common potential biomarkers for the two liver diseases. Correlation networks based on these metabolites were also built for the systemic understanding of these diseases and the possible biological implications are discussed. This metabonomic approach may provide insight into discovery and identification of new diagnostic biomarkers for liver cancer and associated diseases.
Mol Biosyst 2009 Aug
PMID:A metabonomic study of hepatitis B-induced liver cirrhosis and hepatocellular carcinoma by using RP-LC and HILIC coupled with mass spectrometry. 1960 22


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