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)

Elevated glucocorticoid levels are associated with many diseases, including age-related depression, hypertension, Alzheimer's disease, and acquired immunodeficiency syndrome. Cortisol-lowering agents could provide useful complementary therapy for these disorders. We examined the effect of procaine and procaine in a pharmaceutical formulation on adrenal cortical steroid formation. Procaine inhibited dibutyryl cyclic AMP (dbcAMP)-induced corticosteroid synthesis by murine Y1 and human H295R adrenal cells in a dose-dependent manner without affecting basal steroid formation. Treatment of rats with the procaine-based formulation reduced circulating corticosterone levels. This steroidogenesis-inhibiting activity of procaine was not observed in Leydig cells, suggesting that the effect was specific to adrenocortical cells. In search of the mechanism underlying this inhibitory effect on cAMP-induced corticosteroidogenesis, procaine was found to affect neither the cAMP-dependent protein kinase activity nor key proteins involved in cholesterol transport into mitochondria, cytochrome P450 side chain cleavage enzyme expression, and enzymatic activities associated with cholesterol metabolism to final steroid products. However, procaine reduced in a dose-dependent manner the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) activity and the dbcAMP-induced HMG-CoA reductase mRNA levels by affecting mRNA stability. These data suggest that the inhibitory effect of procaine on cAMP-induced corticosteroid formation is due to the reduced synthesis of cholesterol. This modulatory effect of procaine on HMG-CoA reductase mRNA expression was also seen in dbcAMP-stimulated Hepa1-6 mouse liver hepatoma cells. Taken together, these results suggest that procaine may provide a pharmacological means for the control of hormone-induced HMG-CoA reductase mRNA expression and hypercortisolemia.
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PMID:Inhibition of adrenal cortical steroid formation by procaine is mediated by reduction of the cAMP-induced 3-hydroxy-3-methylglutaryl-coenzyme A reductase messenger ribonucleic acid levels. 1456 37

HIP/PAP is a C-type lectin overexpressed in hepatocellular carcinoma (HCC). Pleiotropic biological activities have been ascribed to this protein, but little is known about the function of HIP/PAP in the liver. In this study, therefore, we searched for proteins interacting with HIP/PAP by screening a HCC cDNA expression library. We have identified the RII alpha regulatory subunit of cAMP-dependent protein kinase (PKA) as a partner of HIP/PAP. HIP/PAP and RII alpha were coimmunoprecipitated in HIP/PAP expressing cells. The biological relevance of the interaction between these proteins was established by demonstrating, using fractionation methods, that they are located in a same subcellular compartment. Indeed, though HIP/PAP is a protein secreted via the Golgi apparatus we showed that a fraction of HIP/PAP escaped the secretory apparatus and was recovered in the cytosol. Basal PKA activity was increased in HIP/PAP expressing cells, suggesting that HIP/PAP may alter PKA signalling. Indeed, we showed, using a thymidine kinase-luciferase reporter plasmid in which a cAMP responsive element was inserted upstream of the thymidine kinase promoter, that luciferase activity was enhanced in HIP/PAP expressing cells. Thus our findings suggest a novel mechanism for the biological activity of the HIP/PAP lectin.
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PMID:HIP/PAP, a C-type lectin overexpressed in hepatocellular carcinoma, binds the RII alpha regulatory subunit of cAMP-dependent protein kinase and alters the cAMP-dependent protein kinase signalling. 1537 27

The liver is one of the major target organs of insulin in which the expression of insulin receptor is abundant. We analyzed the effect of AICAR, an AMPK activator, on the expression of insulin receptor in a human hepatoma cell line, HepG2 cells. AICAR treatment for 48 h significantly decreased the expression of the insulin receptor protein in a dose-dependent manner, however, this same effect of AICAR was not observed in either 3T3-L1 adipocytes or CHO cells. The expression of insulin receptor mRNA also decreased after AICAR treatment. In addition, the transcriptional activity of the insulin receptor gene promoter investigated with a luciferase assay was down-regulated by AICAR treatment. Dipyridamole, an adenosine transporter inhibitor, and 5'-amino-5'-deoxyadenosine, an adenosine kinase inhibitor, blocked the effect of AICAR on the down-regulation of the insulin receptor protein, mRNA, and promoter activity. Our findings suggest, for the first time, that AMPK activation could reduce the expression of insulin receptor, at least in part, by a down-regulation of the transcriptional level, and this effect may be liver specific.
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PMID:AICAR, an activator of AMP-activated protein kinase, down-regulates the insulin receptor expression in HepG2 cells. 1569 68

SNARK is a member of the AMPK subfamily of serine/threonine protein kinases. In this study, we examined the regulation of SNARK activity in kidney (BHK, HEK293), pancreatic beta-cell insulinoma (INS-1), hepatocarcinoma (H4IIE) and keratinocyte (NRKC)-derived cell lines in response to diverse cellular stresses. We show that SNARK activity is regulated by glucose- or glutamine-deprivation, induction of endoplasmic reticulum stress by homocysteine or DTT, elevation of cellular AMP and/or depletion of ATP, hyperosmotic stress, salt stress, ultraviolet B radiation and oxidative stress caused by hydrogen peroxide. Moreover, the regulation of SNARK activity in response to cellular stresses depends greatly upon cell type. Furthermore, SNARK activity is downregulated by metformin in a dose- and time-dependent manner in H4IIE cells. These observations support a role for SNARK as a molecular component of the cellular stress response.
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PMID:Regulation of SNARK activity in response to cellular stresses. 1589 79

Because survival and growth of human hepatoma cells are maintained by nutrient, especially glucose, glucose starvation induces acute cell death. The cell death is markedly suppressed by hypoxia, and we have reported involvement of AMP-activated protein kinase-alpha (AMPK-alpha), Akt, and ARK5 in hypoxia-induced tolerance. In the current study we investigated the mechanism of hypoxia-induced tolerance in human hepatoma cell line HepG2. ARK5 expression was induced in HepG2 cells when they were subjected to glucose starvation, and we found that glucose starvation transiently induced Akt and AMPK-alpha phosphorylation and that hypoxia prolonged phosphorylation of both protein kinases. We also found that hypoxia-induced tolerance was partially abrogated by blocking the Akt/ARK5 system or by suppressing AMPK-alpha expression and that suppression of both completely abolished the tolerance, suggesting that AMPK-alpha activation signaling and the Akt/ARK5 system play independent essential roles in hypoxia-induced tolerance. By using chemical compounds that specifically inhibit kinase activity of type I-transforming growth factor-beta (TGF-beta) receptor, we showed an involvement of TGF-beta in hypoxia-induced tolerance. TGF-beta1 mRNA expression was induced by hypoxia in an hypoxia-inducible factor-1alpha-independent manner, and addition of recombinant TGF-beta suppressed cell death during glucose starvation even under normoxic condition. AMPK-alpha, Akt, and ARK5 were activated by TGF-beta1, and Akt and AMPK-alpha phosphorylation, which was prolonged by hypoxia, was suppressed by an inhibitor of type I TGF-beta receptor. Based on these findings, we propose that hypoxia-induced tumor cell tolerance to glucose starvation is caused by hypoxia-induced TGF-beta1 through AMPK-alpha activation and the Akt/ARK5 system.
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PMID:Involvement of transforming growth factor-beta 1 signaling in hypoxia-induced tolerance to glucose starvation. 1601 25

Cyclic AMP (cAMP), one of the most important intracellular second messengers, has been reported to inhibit proliferation of human hepatocellular carcinoma (HCC) cells via negatively regulating p42/44 mitogen-activated protein kinase. Here, we reported that cAMP inhibited the proliferation of HCC BEL-7402 cells via a novel mechanism. Forskolin, an activator of adenylate cyclase, inhibited fetal bovine serum (FBS)-stimulated BEL-7402 cell proliferation in a dose- and time-dependent manner, along with the inhibition of FBS-stimulated serine/threoine protein kinase Akt (also known as PKB) phosphorylation which is required for Akt activation and this effect was mimicked by 8-Br cAMP. Forskolin also inhibited Akt phosphorylation stimulated by other growth factors such as IGF-1, epidermal growth factor, and insulin. These inhibitions were found not only in BEL-7402 cells, but also in another HCC cell line SMMC-7721 cells. Myr-Akt (myristolated-Akt), a constitutively active Akt which was relatively resistant to cAMP inhibition, conferred BEL-7402 cells resistance to cAMP treatment. However, overexpression of Myr-Akt alone was not sufficient to stimulate BEL-7402 cell proliferation. cAMP inhibited FBS-stimulated Akt phosphorylation in a cAMP-dependent protein kinase-dependent manner. Further studies demonstrated that cAMP inhibited FBS-induced membrane localization of 3-phosphoinositide-dependent kinase 1 (PDK-1) which is a required process for PDK-1 to phosphorylate Akt, but had no significant effect on phosphoinositide 3-kinase activity. These results indicate that cAMP inhibition of proliferation of HCC cells is mediated by Akt and cAMP inhibits Akt activation via blocking membrane localization of PDK-1.
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PMID:Cyclic AMP inhibition of proliferation of hepatocellular carcinoma cells is mediated by Akt. 1641 Jul 16

The expression of carbamoylphosphate synthetase-I (CPS), the first and rate-determining enzyme of the urea cycle, is regulated at the transcriptional level by glucocorticoids and glucagon, the latter acting via cyclic AMP (cAMP). The hormonal response is mediated by a distal enhancer located 6.3 kb upstream of the transcription-start site. Within this enhancer, a cAMP-response unit (CRU) is responsible for mediating cAMP-dependent transcriptional activity. The CPS CRU contains binding sites for cAMP-response element (CRE)-binding protein (CRE-BP), forkhead box A (FoxA), CCAAT/enhancer-binding protein (C/EBP), and an unidentified protein P1. To gain insight in the protein-DNA interactions that activate the CPS CRU in living cells, we have employed in vivo footprinting assays. Comparison of the fibroblast cell line Rat-1 and the hepatoma cell lines FTO-2B and WT-8 showed that FoxA binds the CPS CRU constitutively in CPS-expressing cells only. Comparison of FTO-2B and WT-8 hepatoma cells, which only differ in cAMP responsiveness, demonstrated that the binding of the other transcription factors is dependent on cAMP-dependent protein kinase (PKA) activity. Finally, we observed a footprint between the CRE and the P1-binding site in the in vivo footprint assay that was not detectable by in vitro footprint assays, implying a major change in CRU-associated chromatin conformation upon CRU activation. These findings indicate that activation of the CRU is initiated in a tissue-specific manner by the binding of FoxA. When cellular cAMP and glucocorticoid levels increase, CRE-BP becomes activated, allowing the binding of the remaining transcription factors and the transactivation of the CPS promoter.
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PMID:In vivo footprinting of the carbamoylphosphate synthetase I cAMP-response unit indicates important roles for FoxA and PKA in formation of the enhanceosome. 1682 61

LKB1 is a 50 kDa serine/threonine kinase that phosphorylates and activates the catalytic subunit of AMPK at its T-loop residue Thr 172. We prepared adenoviruses expressing the constitutive active (wild-type) form (CA) or dominant negative (kinase inactive, D194A mutant) form (DN) of LKB1 and overexpressed these proteins in cultured myotubes (C2C12 cells) and rat hepatoma cells (FAO cells). When analyzed by immunoblotting with the antibody against Thr172-phosphorylated AMPK, the phosphorylation of AMPK was increased (2.5-fold) and decreased (0.4-fold) in cells expressing CA and DN LKB1, respectively, as compared with Lac-Z expressing control cells. Immunoprecipitation experiments, using isoform-specific antibody, revealed these alterations of AMPK phosphorylation to be attributable to altered phosphorylation of AMPK alpha2, but not alpha1 catalytic subunits, strongly suggesting the alpha2 catalytic subunit to be the major substrate for LKB1 in mammalian cells. In addition, adiponectin or AICAR-stimulated AMPK phosphorylation was inhibited by overexpression of DN LKB1, while phenformin-stimulated phosphorylation was unaffected. These results may explain the difference in AMPK activation mechanisms between AMP and phenformin, and also indicate that AMPK phosphorylation by LKB1 is involved in AMP-stimulated AMPK activation. As a downstream target for AMPK, AICAR-induced glucose uptake and ACCbeta phosphorylation were found to be significantly reduced in DN LKB1 expressing C2C12 cells. The expression of key enzymes for gluconeogenesis, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, was also dependent on LKB1 activities in FAO cells. These results demonstrate that LKB1 is a crucial regulator of AMPK activation in muscle and liver cells and, therefore, that LKB1 activity is potentially of importance to our understanding of glucose and lipid metabolism.
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PMID:LKB1, an upstream AMPK kinase, regulates glucose and lipid metabolism in cultured liver and muscle cells. 1708 19

A lipid droplet (LD)-associated protein, perilipin, is a critical regulator of lipolysis in adipocytes. We previously showed that Comparative Gene Identification-58 (CGI-58), a product of the causal gene of Chanarin-Dorfman syndrome, interacts with perilipin on LDs. In this study, we investigated the function of CGI-58 using RNA interference. Notably, CGI-58 knockdown caused an abnormal accumulation of LDs in both 3T3-L1 preadipocytes and Hepa1 hepatoma cells. CGI-58 knockdown did not influence the differentiation of 3T3-L1 adipocytes but reduced the activity of both basal and cAMP-dependent protein kinase-stimulated lipolysis. In vitro studies showed that CGI-58 itself does not have lipase/esterase activity, but it enhanced the activity of adipose triglyceride lipase. Upon lipolytic stimulation, endogenous CGI-58 was rapidly dispersed from LDs into the cytosol along with small particulate structures. This shift in localization depends on the phosphorylation of perilipin, because phosphorylated perilipin lost the ability to bind CGI-58. During lipolytic activation, LDs in adipocytes vesiculate into micro-LDs. Using coherent anti-Stokes Raman scattering microscopy, we pursued the formation of micro-LDs in single cells, which seemed to occur in cytoplasmic regions distant from the large central LDs. CGI-58 is not required for this process. Thus, CGI-58 facilitates lipolysis in cooperation with perilipin and other factors, including lipases.
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PMID:CGI-58 facilitates lipolysis on lipid droplets but is not involved in the vesiculation of lipid droplets caused by hormonal stimulation. 1730 34

An ethanolic extract of Russian tarragon, Artemisia dracunculus L., with antihyperglycemic activity in animal models was reported to decrease phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression in STZ-induced diabetic rats. A quantitative polymerase chain reaction (qPCR) assay was developed for the bioactivity-guided purification of the compounds within the extract that decrease PEPCK expression. The assay was based on the inhibition of dexamethasone-stimulated PEPCK upregulation in an H4IIE hepatoma cell line. Two polyphenolic compounds that inhibited PEPCK mRNA levels were isolated and identified as 6-demethoxycapillarisin and 2',4'-dihydroxy-4-methoxydihydrochalcone with IC(50) values of 43 and 61 muM, respectively. The phosphoinositide-3 kinase (PI3K) inhibitor LY-294002 showed that 6-demethoxycapillarisin exerts its effect through the activation of the PI3K pathway, similarly to insulin. The effect of 2',4'-dihydroxy-4-methoxydihydrochalcone is not regulated by PI3K and dependent on activation of AMPK pathway. These results indicate that the isolated compounds may be responsible for much of the glucose-lowering activity of the Artemisia dracunculus extract.
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PMID:Polyphenolic compounds from Artemisia dracunculus L. inhibit PEPCK gene expression and gluconeogenesis in an H4IIE hepatoma cell line. 1784 30


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