Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that N-acetylleucine amide, a derivative of L-leucine, inhibits leucine-induced p70(S6k) activation in a rat hepatoma cell line. In the present study, we investigated whether N-acetylleucine amide is capable of inhibiting amino acid-mTOR signaling. N-Acetylleucine amide caused cell cycle arrest at G1 stage in Jurkat cells, a human leukemia T cell line, concomitant with the inhibition of serum-induced p70(S6k) activation and p27 degradation. Treatment of Jurkat cells with this compound also exhibited dephosphorylation of retinoblastoma protein. These effects are similar to the inhibitory effects of rapamycin on amino acid-mTOR signaling pathway and suggest that N-acetylleucine amide acts as a rapamycin-like reagent to inhibit cell cycle progression in Jurkat cells.
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PMID:Inhibition of amino acid-mTOR signaling by a leucine derivative induces G1 arrest in Jurkat cells. 1256 77

Rosiglitazone (RSG), an agonist of peroxisome proliferator-activated receptor gamma (PPARgamma), induces minor toxicity in humans relative to another PPARgamma agonist, troglitazone (TRO). In contrast, recent reports suggest that RSG causes growth arrest and apoptosis of normal and cancerous cells. Therefore, in this study, we investigated the relative toxicities of TRO and RSG on three different hepatoma cell lines, and observed that TRO, but not RSG, was cytotoxic. Additionally, we studied the mechanism by which TRO induced damage to HepG2 hepatoma cells. Our results indicated that TRO increased the levels of p53, p27, and p21, while it reduced the levels of cyclin D1 and phospho-Rb in a time-dependent manner. Increased p27 and p21 levels coincided with reduced activities of cell cycle dependent kinases (cdk) such as cdk2- and cyclin A-protein kinases 24 h after TRO treatment. These results demonstrate that TRO, but not RSG, causes G1 arrest of hepatoma cells, most likely through changing the levels of cell cycle regulators. Furthermore, because RSG did not affect the levels of cell cycle regulators, TRO-mediated growth inhibition appears independent of PPARgamma activation.
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PMID:Troglitazone but not rosiglitazone induces G1 cell cycle arrest and apoptosis in human and rat hepatoma cell lines. 1259 59

Increasing evidence has confirmed that ligands for peroxisome proliferator-activated receptor gamma (PPARgamma) exhibit antitumoral effects through inhibition of cell proliferation and induction of cell differentiation in several malignant neoplasms. Recently, we have documented the accumulation of a cyclin-dependent kinase inhibitor, p27(Kip1), as well as an unexpected accumulation in cyclin E in G1-arrested human hepatoma cells treated with the PPARgamma ligand troglitazone. Simultaneous accumulations in both p27(Kip1) and cyclin E are known to be characteristic phenotypes in cells derived from mice lacking Skp2, an F-box protein component of the SCF ubiquitin-ligase complex. Thus, the aim of the present study was to assess whether Skp2 might be involved in the down-regulation of p27(Kip1) in troglitazone-treated human hepatoma cells. A striking decrease in Skp2 expression and a reciprocal increase in p27(Kip1) expression were found in troglitazone-treated hepatoma cells but not in those cells treated with other PPARgamma ligands such as pioglitazone and ciglitazone. Quantitative real-time RT-PCR analysis showed that troglitazone down-regulated Skp2 at the mRNA levels. Consistently, ectopic overexpression in Skp2 brought resistance to troglitazone, resulting in a decreased population of arrested cells at the G1 phase compared with that in the mock-transfected cells. In surgically resected hepatocellular carcinoma (HCC) tissue, an increased expression in Skp2 was found in both the moderately differentiated HCCs and the poorly differentiated HCCs. In conclusion, troglitazone attenuated Skp2 expression, thereby promoting p27(Kip1) accumulation in human hepatoma cells. This therapeutic potential of the ligand may lead to new cell-cycle-based antitumor strategies for advanced HCCs.
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PMID:Troglitazone induces p27Kip1-associated cell-cycle arrest through down-regulating Skp2 in human hepatoma cells. 1271 89

Although cooperative interactions between growth factors and integrins, cell surface receptors for extracellular matrices (ECM), have been reported, little is known about the interaction between hepatocyte growth factor (HGF) and integrin in hepatoma cells. We investigated the effects and mechanisms of integrin on the proliferation of hepatoma cells regulated by HGF. Human HepG2 hepatoma cells stably transfected with beta 1-integrin were treated with HGF and compared with parental and mock-transfected control cells. Cell proliferation and expression of cyclin-dependent kinase (Cdk) inhibitors and S-phase kinase-associated protein 2 (Skp2), were investigated. HGF dose-dependently suppressed the proliferation of parental and mock-transfected HepG2 cells. However, cells overexpressing beta 1-integrin exhibited increased proliferation in response to HGF. Although HGF increased p27 and decreased Skp2 expression in the parental and mock-transfected cells, the p27 and Skp2 levels in cells overexpressing beta 1-integrin were not altered by HGF. Interestingly, HepG2 cells overexpressing beta 1-integrin showed increased Skp2 expression. Furthermore, HGF did not reduce the proliferation of HepG2 cells transfected with antisense p27 or sense Skp2. Thus, HGF suppresses HepG2 cell proliferation by directly increasing p27 expression and indirectly decreasing Skp2 expression, and beta 1-integrin modulates the responsiveness of hepatoma cells to HGF via a p27-dependent manner by increasing Skp2. In conclusion, these results strongly suggest that integrin-mediated signals from the ECM can modulate growth factor-mediated signals in hepatoma cells, and may contribute to the growth of hepatocellular carcinomas.
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PMID:Mechanism of beta 1-integrin-mediated hepatoma cell growth involves p27 and S-phase kinase-associated protein 2. 1288 71

Expression of cyclin dependent kinase (Cdk) inhibitor p27(Kip1), which blocks cell cycle progression from G(1) to S phase, can be regulated via multiple mechanisms including transcription, protein degradation, and translation. Recently, it was shown that p27(Kip1) plays an important role in the cellular response to hypoxia. However, the mechanisms involved in the hypoxia-induced regulation of p27(Kip1) expression are still not clear. In this study, we compare the expression of p27(Kip1) in two related murine hepatoma cell lines, Hepa-1 and c4. Hepa-1 produces functional aryl hydrocarbon receptor nuclear translocator (ARNT). c4 cells are derived from Hepa-1, but are ARNT deficient. Interestingly, we observed cell line-dependent effects of hypoxia on the expression of p27(Kip1). The level of p27(Kip1) protein in Hepa-1 cells is enhanced by hypoxia, but is reduced by hypoxia in c4 cells. Further investigation demonstrated that hypoxia-induced, ARNT-mediated, transactivation of the p27(Kip1) gene in Hepa-1 cells is responsible for the increase in p27(Kip1) protein. Once c4 cells were stably transfected with the wild type ARNT gene, a hypoxia-induced increase in p27(Kip1) mRNA was observed and reduction of p27(Kip1) protein caused by hypoxia was blocked. Hence, our data indicate that ARNT is involved in transcriptional upregulation of the p27(Kip1) gene under hypoxic conditions.
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PMID:Cyclin dependent kinase inhibitor p27(Kip1) is upregulated by hypoxia via an ARNT dependent pathway. 1452 89

In our study, we examined whether human hepatocellular carcinoma (HCC) expresses peroxisome proliferator-activated receptor gamma (PPARgamma) and the effects of PPAR gamma activation by its selective ligands on cell growth and cell invasion in HCC cells. RT-PCR and Western blot analysis revealed that HCC-derived cell lines, HepG2 and HLF, express PPARgamma mRNA and protein. Luciferase assay in HLF cells showed that troglitazone, a selective ligand for PPAR gamma, transactivated the transcription of a peroxisome proliferator response element-driven promoter in a dose-dependent manner, suggesting that the expressed PPARgamma functions as a transcriptional factor. Not only troglitazone but pioglitazone dose-dependently inhibited cell growth in HepG2 and HLF cells. Invasion assay using a transwell chamber demonstrated that troglitazone also inhibited cell invasion in HCC cells. To examine the mechanism of the troglitazone-induced growth inhibition, we determined p27(Kip1), a cyclin dependent kinase inhibitor, expression by Western blot analysis in troglitazone-treated HLF cells. Troglitazone increased p27(Kip1) in time- and dose-dependent manners, suggesting that p27(Kip1) may be involved in the growth inhibition by troglitazone in HLF cells. To further examine the mechanism of the troglitazone-induced p27(Kip1) protein accumulation, 2 major systems for regulation of p27(Kip1) protein, proteasome activity and Skp2, an F-box protein that targets p27(Kip1) for degradation, were evaluated. Troglitazone potently inhibited proteasome activity and decreased Skp2 protein levels. All these results suggest that human HCC cells express functional PPAR gamma and PPARgamma activation resulted in growth inhibition. The growth inhibition was mediated by p27(Kip1) accumulation, which is induced by both inhibition of ubiquitylation of p27(Kip1) and reduction of degradation activity of p27Kip1 by proteasome.
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PMID:Growth arrest by troglitazone is mediated by p27Kip1 accumulation, which results from dual inhibition of proteasome activity and Skp2 expression in human hepatocellular carcinoma cells. 1461 13

Although arsenic exposure causes liver disease and/or hepatoma, little is known about molecular mechanisms of arsenic-induced liver toxicity or carcinogenesis. We investigated the effects of arsenic on expression of cancer-related genes in a rat liver following subchronic exposure to sodium arsenate (1, 10, 100 ppm in drinking water), by using real-time quantitative RT-PCR and immunohistochemical analyses. Arsenic accumulated in the rat liver dose-dependently and caused hepatic histopathological changes, such as disruption of hepatic cords, sinusoidal dilation, and fatty infiltration. A 1-month exposure to arsenic significantly increased hepatic mRNA levels of cyclin D1 (10 ppm), ILK (1 ppm), and p27(Kip1) (10 ppm), whereas it reduced mRNA levels of PTEN (1 ppm) and beta-catenin (100 ppm). In contrast, a 4-month arsenic exposure showed increased mRNA expression of cyclin D1 (100 ppm), ILK (1 ppm), and p27(Kip1) (1 and 10 ppm), and decreased expression of both PTEN and beta-catenin at all 3 doses. An immunohistochemical study revealed that each protein expression accords closely with each gene expression of mRNA level. In conclusion, subchronic exposure to inorganic arsenate caused pathological changes and altered expression of cyclin D1, p27(Kip1), ILK, PTEN, and beta-catenin in the liver. This implies that arsenic liver toxicity involves disturbances of some cancer-related molecules.
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PMID:Subchronic exposure to arsenic through drinking water alters expression of cancer-related genes in rat liver. 1471 50

mRNA abundance for a number of genes is increased by amino acid limitation. From an array screening study in HepG2 human hepatoma cells, it was established that one set of genes affected by amino acid availability is the set associated with cell-cycle control. The present study describes the increased expression of both mRNA and protein for the cyclin-dependent kinase inhibitors p21 and p27 in response to deprivation of HepG2 cells for a single essential amino acid, histidine. The increase in p21 and p27 mRNA content depended on de novo protein synthesis and involved a post-transcriptional mRNA stabilization component. For p21, increase in mRNA by histidine depletion appeared to be independent of p53 transactivation, and the absolute level of p53 protein was unaffected by this treatment. Histidine limitation caused an increase in the phosphorylation of ERK1/ERK2 (extracellular-signal-regulated kinase), and inhibition of the ERK signal transduction pathway resulted in a reduction in the starvation-dependent increase in p21 mRNA. Blockade of the phosphoinositide 3-kinase and mTOR (mammalian target of rapamycin) pathways also blunted the increase in p21 mRNA content. These results document the amino acid-dependent control of the synthesis of specific cell-cycle regulators and help to explain the block at G1 phase after amino acid limitation.
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PMID:Induction of p21 and p27 expression by amino acid deprivation of HepG2 human hepatoma cells involves mRNA stabilization. 1471 82

The p53 tumor suppressor gene product plays an important role in the regulation of apoptosis. Transforming growth factor beta1 (TGF-beta1)-induced apoptosis in hepatic cells is associated with reduced expression of the retinoblastoma protein (pRb) and subsequent E2F-1-activated expression of apoptosis-related genes. In this study, we explored the potential role of p53 in TGF-beta1-induced apoptosis. HuH-7 human hepatoma cells were either synchronized in G1, S and G2/M phases, or treated with 1 nM TGF-beta1. The results indicated that greater than 90% of the TGF-beta1-treated cells were arrested in G1 phase of the cell cycle. This was associated with enhanced p53 dephosphorylation and p21(Cip1/Waf1) expression, which coincided with decreased Cdk2, Cdk4, and cyclin E expression, compared with synchronized G1 cells. In addition, p53 dephosphorylation coincided with caspase-3 activation, and translocation of p21(Cip1/Waf1) and p27(Kip1) into the cytoplasm, all of which were suppressed by caspase inhibition of TGF-beta1-induced apoptosis. Finally, phosphatase inhibition and pRb overexpression partially inhibited p53-mediated apoptosis. In conclusion, the results demonstrated that TGF-beta1-induced p53 dephosphorylation is associated with caspase-3 activation, and cytosolic translocation of p21(Cip1/Waf1) and p27(Kip1), resulting in decreased expression of Cdks and cyclins. Further, p53 appears to mediate TGF-beta1-induced apoptosis downstream of the pRb/E2F-1 pathway.
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PMID:p53 dephosphorylation and p21(Cip1/Waf1) translocation correlate with caspase-3 activation in TGF-beta1-induced apoptosis of HuH-7 cells. 1500 18

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Here, we provide evidence that the Forkhead Box (Fox) m1b (Foxm1b or Foxm1) transcription factor is essential for the development of HCC. Conditionally deleted Foxm1b mouse hepatocytes fail to proliferate and are highly resistant to developing HCC in response to a Diethylnitrosamine (DEN)/Phenobarbital (PB) liver tumor-induction protocol. The mechanism of resistance to HCC development is associated with nuclear accumulation of the cell cycle inhibitor p27(Kip1) protein and reduced expression of the Cdk1-activator Cdc25B phosphatase. We showed that the Foxm1b transcription factor is a novel inhibitory target of the p19(ARF) tumor suppressor. Furthermore, we demonstrated that conditional overexpression of Foxm1b protein in osteosarcoma U2OS cells greatly enhances anchorage-independent growth of cell colonies on soft agar. A p19(ARF) 26-44 peptide containing nine D-Arg to enhance cellular uptake of the peptide was sufficient to significantly reduce both Foxm1b transcriptional activity and Foxm1b-induced growth of U2OS cell colonies on soft agar. These results suggest that this (D-Arg)(9)-p19(ARF) 26-44 peptide is a potential therapeutic inhibitor of Foxm1b function during cellular transformation. Our studies demonstrate that the Foxm1b transcription factor is required for proliferative expansion during tumor progression and constitutes a potential new target for therapy of human HCC tumors.
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PMID:Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. 1508 32


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