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)

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and highly resistant to available chemotherapies. Mammalian target of rapamycin (mTOR) functions to regulate protein translation, angiogenesis and cell cycle progression in many cancers including HCC. In the present study, subcutaneous patient-derived HCC xenografts were used to study the effects of an mTOR inhibitor, RAD001 (everolimus), on tumour growth, apoptosis and angiogenesis. We report that oral administration of RAD001 to mice bearing patient-derived HCC xenografts resulted in a dose-dependent inhibition of tumour growth. RAD001-induced growth suppression was associated with inactivation of downstream targets of mTOR, reduction in VEGF expression and microvessel density, inhibition of cell proliferation, up-regulation of p27(Kip1) and down-regulation of p21(Cip1/Waf1), Cdk-6, Cdk-2, Cdk-4, cdc-25C, cyclin B1 and c-Myc. Our data indicate that the mTOR pathway plays an important role in angiogenesis, cell cycle progression and proliferation of liver cancer cells. Our study provides a strong rationale for clinical investigation of mTOR inhibitor RAD001 in patients with HCC.
J Cell Mol Med 2009 Jul
PMID:RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma. 1846 52

The identification of cancer genes differentially expressed in hepatocellular carcinoma (HCC) plays an important role in understanding the molecular mechanisms of hepatocarcinogenesis. Here, ARHI gene expression was analyzed by real-time RT-PCR and it was significantly downregulated in 33 of the 42 (78.6%, more than two folds) HCC specimens compared with adjacent noncancerous livers (P < 0.01). In addition, ARHI expression was reduced in some HCC samples at protein level confirmed by immunohistochemistry. Furthermore, our data suggested that the overexpression of ARHI can significantly inhibit cell growth and colony formation of Hep3B cells (P < 0.01), whilst silencing endogenous ARHI gene by RNAi could promote cell growth of Huh-7 and Focus. LOH of microsatellite markers D1S2806 and D1S2803 was only found in 2.4% (1 of 42 HCCs) of HCC cases. The expression of ARHI was obviously re-expressed in some HCC cells, Bel-7402, Bel-7405, QGY-7703 and Hep3B, by a demethylation agent, 5-aza-2'-deoxycytidine (DAC). DNA hypermethylation within ARHI promoter was identified in 47.1% of HCC specimens without ARHI expression. Our current observations provide evidences that ARHI downregulated in HCCs could play a role in liver cancer via acting as a tumor suppressor gene, which mainly was triggered by the epigenetic events in HCC specimens.
Mol Carcinog 2009 Feb
PMID:ARHI, as a novel suppressor of cell growth and downregulated in human hepatocellular carcinoma, could contribute to hepatocarcinogenesis. 1861 97

Transforming growth factor-beta (TGF-beta) has been shown to induce apoptotic cell death in normal and transformed hepatocytes. We recently identified tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) as an important mediator of TGF-beta-induced apoptosis in hepatoma cells. In this study, we have further explored the mechanism by which TGF-beta up-regulates TRAIL expression. The 5'-flanking region of the TRAIL gene was isolated and characterized. Deletion mutants of the 5'-untranslated region of the TRAIL gene revealed a region comprising nucleotides -1950 to -1100 responsible for TRAIL induction following treatment with TGF-beta. Within this region, we have identified an activator protein-1 (AP-1) site indispensable for TGF-beta-mediated induction of TRAIL. Activation of this AP-1 site is mediated by a JunD.FosB heterodimer. Expression of DNSmad4, DNJunD, or DNFosB significantly impairs TGF-beta-mediated activation of the TRAIL promoter. Furthermore, with tRNA interference targeting Smad4, junD, FosB, we could abolish TRAIL expression and, subsequently, TGF-beta-induced TRAIL-mediated apoptosis in hepatoma cells. Our results reveal a new AP-1 site within the TRAIL promoter functionally involved in TGF-beta-induced TRAIL expression and apoptosis in hepatomas and thus provide evidence for the underlying mechanism by which TGF-beta might regulate cell death in liver cancer.
Mol Cancer Res 2008 Jul
PMID:Transforming growth factor-beta-mediated tumor necrosis factor-related apoptosis-inducing ligand expression and apoptosis in hepatoma cells requires functional cooperation between Smad proteins and activator protein-1. 1864 81

A boy who was diagnosed with methylmalonic aciduria (MMA) at the age of 10 days developed persistent hepatomegaly and raised transaminases from the age of 4 years. He was subsequently diagnosed with Leigh syndrome and required a kidney transplantation for end-stage renal failure. A massive hepatoblastoma led to his death by the age of 11 years. Methylmalonyl-CoA mutase activity was undetectable on both cultured skin fibroblasts and kidney biopsy and multiple respiratory chain deficiency was demonstrated in the kidney. Mitochondrial dysfunction and/or post-transplant immunosuppressive therapy should be considered as a possible cause of liver cancer in this patient.
Mol Genet Metab
PMID:Liver hepatoblastoma and multiple OXPHOS deficiency in the follow-up of a patient with methylmalonic aciduria. 1867 66

The detection and quantification of specific proteins in complex mixtures is a major challenge for proteomics. For example, the development of disease-related biomarker panels will require fast and efficient methods for obtaining multiparameter protein profiles. We established a high throughput, label-free method for analyzing serum using surface plasmon resonance imaging of antibody microarrays. Microarrays were fabricated using standard pin spotting on bare gold substrates, and samples were applied for binding analysis using a camera-based surface plasmon resonance system. We validated the system by measuring the concentrations of four serum proteins using part of a 792-feature microarray. Transferrin concentrations were measured to be 2.1 mg/ml in human serum and 1.2 mg/ml in murine serum, which closely matched ELISA determinations of 2.6 and 1.2 mg/ml, respectively. In agreement with expected values, human and mouse albumin levels were measured to be 24.3 and 23.6 mg/ml, respectively. The lower limits of detection for the four measurements ranged from 14 to 58 ng/ml or 175 to 755 pm. Where purified target proteins are not available for calibration, the microarrays can be used for relative protein quantification. We used the antibody microarray to compare the serum protein profiles from three liver cancer patients and three non-liver cancer patients. Hierarchical clustering of the serum protein levels clearly distinguished two distinct profiles. Thirty-nine significant protein changes were detected (p < 0.05), 10 of which have been observed previously in serum. alpha-Fetoprotein, a known liver cancer marker, was observed to increase. These results demonstrate the feasibility of this high throughput approach for both absolute and relative protein expression profiling.
Mol Cell Proteomics 2008 Dec
PMID:Quantitative serum proteomics from surface plasmon resonance imaging. 1867 62

Vitamins play essential roles in cellular reactions and maintain human health. Recent studies have revealed that some vitamins including D3, B6 and K2 and their derivatives have an anti-cancer effect. As a mechanism, their inhibitory effect on cancer-related angiogenesis has been demonstrated. Vitamin K2 (menaquinones) has an anti-cancer effect in particular for hepatic cancer and inhibits angiogenesis. In the current study, we demonstrated that sole vitamin K3 (menadione) selectively inhibits the in vitro activity of eukaryotic DNA polymerase gamma, which is a mitochondrial DNA polymerase, and suppresses angiogenesis in a rat aortic ring model. The anti-angiogenic effect of vitamin K3 has been shown in angiogenesis models using human umbilical vein endothelial cells (HUVECs) with regard to HUVEC growth, tube formation on reconstituted basement membrane and chemotaxis. These results suggest that vitamin K3 may be a potential anti-cancer agent like vitamin K2.
Int J Mol Med 2008 Sep
PMID:Inhibitory effects of vitamin K3 on DNA polymerase and angiogenesis. 1869 99

c-raf is a serine-threonine kinase and a downstream effector of ras signaling. This kinase plays an essential role in cell proliferation, differentiation, and apoptosis. In the past, we reported induction of c-raf gene expression in rat liver cancer on treatment with a mixture of aryl hydrocarbon receptor (AhR) agonists. This prompted our interest in investigating the role of AhR in the transcriptional regulation of c-raf. Initially, we cloned the rat c-raf promoter and sequenced the genomic DNA and cDNA by Southern blotting and capillary electrophoresis. Then, a genetic algorithm was applied to search for putative AhR-binding sites. DNA-binding activity of AhR was confirmed by electromobility shift assay. We also studied c-raf gene expression in rat hepatoma cell lines with functional and/or devoid AhR and in primary human and rat hepatocyte cultures. Overall, we identified five and three AhR-binding sites in the human and rat c-raf gene, respectively. Treatment of hepatocyte cultures with the AhR antagonist resveratrol reduced DNA binding of AhR. Only rat hepatoma cells with functional AhR responded to 1 nmol/L 2,3,7,8-tetrachlorodibenzo-p-dioxin treatment with >10-fold c-raf mRNA induction. Treatment of human and rat hepatocyte cultures with various AhR-activating chemicals resulted in induction of c-raf gene expression, albeit at different levels. Taken collectively, we show AhR to be a master regulator of c-raf and propose cross-talk between AhR and the mitogen-activated protein kinase signaling pathway in chemically induced hepatocarcinogenesis.
Mol Cancer Res 2008 Aug
PMID:Cross-talk between aryl hydrocarbon receptor and mitogen-activated protein kinase signaling pathway in liver cancer through c-raf transcriptional regulation. 1870 64

Heat shock protein 90 (Hsp90) is a molecular chaperone involved in folding, assembly, maturation, and stabilization of the client proteins that regulate survival of malignant cells. As previous reports correlate high Hsp90 expression with decreased survival in breast cancer, Hsp90 may be a favorable target for investigational therapy in breast cancer. In our study, we have examined the response of a panel of both BRCA1-null (UACC 3199, HCC 1937, and MBA-MD-436) and BRCA1-wt breast cancer cell lines (MCF-7, MBA-MD-157, and Hs578T) to determine the proteins governing response to Hsp90 inhibitor 17-allyloamino-17-demethoxy-geldanamycin. On treatment with the drug, cells arrested at G(2)-M phase and entered aberrant mitosis in a BRCA1-dependent manner. Failure to arrest the cells at or before mitosis resulted in formation of micronucleated cells, aberrant segregation of chromosomes, microtubule misalignment, and multicentrosomes, leading in eventual mitotic catastrophe cell death. Our observations show that BRCA1 mediates G(2)-M transition mainly through chek1 on 17-allyloamino-17-demethoxy-geldanamycin treatment.
Mol Cancer Ther 2008 Aug
PMID:Mitotic catastrophe cell death induced by heat shock protein 90 inhibitor in BRCA1-deficient breast cancer cell lines. 1872 83

Anthocyanins extracted from the berries of Phillyrea latifolia L., Pistacia lentiscus L., and Rubia peregrina L., three evergreen shrubs widely distributed in the Mediterranean area, were examined for their antioxidant and anticancer activity. The P. lentiscus anthocyanins showed the highest H(2)O(2) and 1,1-diphenyl-2-picryl-hydrazil radical scavenging effects, indicating that these compounds can be considered as an alternative source of natural antioxidants for food and pharmaceutical products. Here, we also report a novel function of anthocyanins: the induction of autophagy, a process of subcellular turnover involved in carcinogenesis. Autophagy was characterized by the up-regulation of eIF2alpha, an autophagy inducer, and down-regulation of mTOR and Bcl-2, two autophagy inhibitors. This led to the enhanced expression of LC3-II, an autophagosome marker in mammals, and monodansylcadaverine incorporation into autolysosomes. Anthocyanin-induced autophagy switched to apoptosis, as shown by the activation of Bax, cytochrome c and caspase 3, terminal deoxynucleotide transferase-mediated dUTP nick-end labeling-positive fragmented nuclei, and cells with sub-G(1) DNA content, which were prevented by z-VAD. Inhibition of autophagy by either 3-methyladenine or Atg5 small interfering RNA enhanced anthocyanin-triggered apoptosis. This provided evidence that autophagy functions as a survival mechanism in liver cancer cells against anthocyanin-induced apoptosis and a rationale for the use of autophagy inhibitors in combination with dietary chemopreventive agents.
Mol Cancer Ther 2008 Aug
PMID:Autophagy inhibition enhances anthocyanin-induced apoptosis in hepatocellular carcinoma. 1872 93

Phloretin (Ph), which can be obtained from apples, apple juice, and cider, is a known inhibitor of the type II glucose transporter (GLUT2). In this study, real-time PCR analysis of laser-capture microdissected (LCM) human hepatoma cells showed elevated expression (>5-fold) of GLUT2 mRNA in comparison with nonmalignant hepatocytes. In vitro and in vivo studies were performed to assess Ph antitumor activity when combined with paclitaxel (PTX) for treatment of human liver cancer cells. Inhibition of GLUT2 by Ph potentiated the anticancer effects of PTX, resensitizing human liver cancer cells to drugs. These results demonstrate that 50-150 microM Ph significantly potentiates DNA laddering induced in Hep G2 cells by 10 nM PTX. Activity assays showed that caspases 3, 8, and 9 are involved in this apoptosis. The antitumor therapeutic efficacy of Ph (10 mg/kg body weight) was determined in cells of the SCID mouse model that were treated in parallel with PTX (1 mg/kg body weight). The Hep G2-xenografted tumor volume was reduced more than fivefold in the Ph + PTX-treated mice compared to the PTX-treated group. These results suggest that Ph may be useful for cancer chemotherapy and chemoprevention.
Mol Carcinog 2009 May
PMID:Apple polyphenol phloretin potentiates the anticancer actions of paclitaxel through induction of apoptosis in human hep G2 cells. 1876 70


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