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

The sphingomyelin pathway is a newly described signal transduction pathway mediating the action of several cytokines including tumor necrosis factor-alpha (TNF). TNF was recently shown to interfere with insulin-induced tyrosine phosphorylation of the insulin receptor substrate-1 (IRS-1). In this work we examined the possible effect of direct activation of the sphingomyelin pathway on insulin-induced tyrosine phosphorylation of IRS-1. Incubation of the insulin-sensitive rat hepatoma Fao cells with bacterial sphingomyelinase (SMase) that causes membrane hydrolysis of sphingomyelin led to a time- and dose-dependent decrease in insulin-induced tyrosine phosphorylation of IRS-1. The effect was apparent after 10 min of incubation and with a dose of 10 milliunits/ml SMase. It was not associated with a decrease in insulin receptor autophosphorylation. In addition, SMase treatment interrupted the association of the 85-kDa catalytic subunit of phosphatidylinositol 3-kinase with IRS-1. A similar impact on IRS-1 tyrosine phosphorylation was observed after addition of cell-permeable ceramide analogs (C2 and C6). Comparable changes in IRS-1 tyrosine phosphorylation and electrophoretic mobility were found after exposure of cells to either TNF, SMase, or ceramide. Our findings suggest that TNF may utilize the sphingomyelin pathway in its effect on the insulin-stimulated tyrosine phosphorylation of IRS-1.
 ...
PMID:Sphingomyelinase and ceramide suppress insulin-induced tyrosine phosphorylation of the insulin receptor substrate-1. 862 23

Members of the Janus kinase (Jak) family of protein tyrosine kinases have recently been implicated in the proximal signal transduction events of cytokine receptors. Jak3, a newly discovered member of this family, is believed to be normally limited in its expression to cells of the lymphoid and myeloid lineages. Herein we show that Jak3 is expressed in primary human vascular cells, as well as other non-lymphoid and non-myeloid cell types. Reverse transcriptase-polymerase chain reaction and Northern blot analysis revealed that Jak3 mRNA was expressed at low levels in human umbilical vein endothelial cells (HUVEC), human aortic smooth muscle cells (HASMC), A549 (human lung carcinoma), and DLD-1 (human colon adenocarcinoma) cells. Higher basal levels of Jak3 mRNA were detected in HMEC-1 (human microvascular cell line) and HepG2 (human hepatocellular carcinoma) cells. Jak3 mRNA expression was induced in HUVEC, HMEC-1, and HASMC by treatment with interleukin-1beta, tumor necrosis factor-alpha, interferon-gamma, and lipopolysaccharide. Jak3 protein was detectable at low levels in untreated HMEC-1, and these levels increased significantly with cytokine treatment. Furthermore, Jak3 protein was phosphorylated upon treatment of these cells with interleukin-4. This work shows that Jak3 is expressed or inducible in human vascular endothelial, vascular smooth muscle, and other non-lymphoid and non-myeloid cells, suggesting a broader role for Jak3 in the cytokine signal transduction of these cells.
 ...
PMID:Expression of Janus kinase 3 in human endothelial and other non-lymphoid and non-myeloid cells. 866 78

We studied the effect a variety of hormones and chemical stimuli on the activity of low Km aldehyde dehydrogenase (ALDH) in rat H4IIEC3 hepatoma cells and ALDH activity in human HuH7 hepatoma cells. The low Km enzyme in H4IIEC3 cells reflects ALDH2 activity, and the ALDH activity in HuH7 likely represents ALDH5. Of the steroid hormone family, thyroid hormone, progesterone, and dihydrotestosterone increased low Km ALDH activity approximately 50%, whereas dexamethasone and estradiol had little effect. Insulin decreased the activity of low Km ALDH. None of these hormones affected the activity of ALDH in HuH7 cells. Among second messengers, 8-bromo-cAMP and A23187 increased low Km ALDH activity; HuH7 ALDH activity again was unchanged. Exposure of the cells to 22 mM ethanol reduced low Km activity by approximately 20%, whereas hydrogen peroxide, tumor necrosis factor-alpha, and interleukin-1 beta had little effect. Ultraviolet light increased the HuH7 ALDH activity. Retinaldehyde or retinolc acid reduced the HuH7 ALDH activity, but had no effect on low Km ALDH activity. These data suggest that low Km ALDH2 can be regulated by hormones and may not be constitutive as previously thought, and that the HuH7 ALDH is regulated differently.
 ...
PMID:Hormonal and chemical influences on the expression of class 2 aldehyde dehydrogenases in rat H4IIEC3 and human HuH7 hepatoma cells. 874 3

Rat Kupffer cell (KC)-mediated cytotoxicity against both the syngeneic hepatoma cell line AH70 and hepatocytes was evaluated by changes in mitochondrial function, and the possible role of ICAM-1/CD18 in the interaction between the cells was studied. Rhodamine 123 fluorescence, a marker of the mitochondrial membrane potential, decreased in AH70 cells after co-culture with CK, while that in hepatocytes was unchanged by co-culture. This decrease was blocked by anti-ICAM-1 anti-CD18 and the inhibition of nitric oxide synthesis. Cytometric studies demonstrated that ICAM-1 expression on AH70 cells increased after addition of IFN-gamma, IL-1beta, tumor necrosis factor (TNF)-alpha or KC, while in hepatocytes ICAM-1 was not increased. Anti-ICAM-1 pretreatment inhibited the increase in ICAM-1 expression and the decrease in rhodamine 123 fluorescence on AH70 cells after co-culture with KC. CD18 on KC was increased only after co-culture with AH70. TNF-alpha but not IFN-gamma was detected in the supernatant of co-culture between KC and AH70 cells, and this production was partially inhibited by anti-ICAM-1 and anti-CD18. The activity of inducible nitric oxide synthase in Kupffer cells and the levels of nitrites and nitrates in the co-culture supernatant increased over time, and this increase was attenuated either by addition of NO synthesis inhibitors, anti-ICAM-1 or anti-CD18. These results indicate that the rat KC causes mitochondrial dysfunction in cancer cells via the production of NO and cell-to-cell adhesion via ICAM-1/CD18 has an important role in this cytotoxic process.
 ...
PMID:Kupffer cell-mediated cytotoxicity against hepatoma cells occurs through production of nitric oxide and adhesion via ICAM-1/CD18. 875 62

Human hepatocarcinoma HepG2 cells are known to be insensitive to tumor necrosis factor (TNF) cytotoxicity. In this report, preliminary washing of HepG2 cells with serum-free medium to remove endogenous and exogenous alpha-fetoprotein (AFP) from the cultivation medium transfers cells from the TNF-resistant to the TNF-sensitive state without addition of any transcriptional inhibitors. HepG2 cells sensitized to by washing again became TNF-resistant after their treatment with exogenous AFP. Protective AFP activity against TNF-induced cytotoxicity directly depends on the AFP/TNF concentration ratio, demonstrating biphasic AFP activity. Our data show that 0.2 mg/ml of AFP acts synergistically to enhance cytotoxicity of suboptimal TNF doses. In contrast, the same AFP dose significantly attenuates the cytotoxicity of high TNF doses. It is concluded that AFP can function as a protective factor against TNF cytotoxicity in human hepatoma cells. These observations suggest that AFP secretion by certain tumor cells allows a highly flexible regulation of TNF cytotoxicity, dependent on the amount of endogenous AFP.
 ...
PMID:Alpha-fetoprotein as a TNF resistance factor for the human hepatocarcinoma cell line HepG2. 898 23

It has been proposed that immunoregulatory cytokines play a role in the onset and development of cancer cachexia, although evidence supporting this theory remains inconclusive. In the present study, SCID mice were implanted with one of two tumor cell lines known to induce weight loss in rats. Growth of the Morris 7777 hepatoma was associated with weight loss as well as increased levels of tumor necrosis factor and interleukins 1 and 6 in spleen cells of tumor-bearing mice. Growth of the MCA sarcoma did not induce weight loss, nor did it increase cytokine expression in spleen cells of tumor-bearing mice. We conclude that increased cytokine expression is associated with weight loss in tumor-bearing SCID mice, and immune activation for cytokine expression does not require the presence of T or B cells.
 ...
PMID:Tumor growth, weight loss and cytokines in SCID mice. 902 35

The "long pentraxins" are an emerging family of genes that have conserved in their carboxy-terminal halves a pentraxin domain homologous to the prototypical acute phase protein pentraxins (C-reactive protein and serum amyloid P component) and acquired novel amino-terminal domains. In this report, a genomic fragment of 1371 nucleotides from the human "long pentraxin" gene PTX3 is characterized as a promoter on tumor necrosis factor-alpha (TNFalpha) and interleukin (IL)-1beta exposure in transfected 8387 human fibroblasts by chloramphenicol acetyltransferase and RNase protection assays. In the same cells, the PTX3 promoter does not respond to IL-6 stimulation. Furthermore, IL-1beta and TNFalpha responsiveness is not seen in the Hep 3B hepatoma cell line. The minimal promoter contains one NF-kappaB element which is shown to be necessary for induction and able to bind p50 homodimers and p65 heterodimers but not c-Rel. Mutants in this site lose the ability to bind NF-kappaB proteins and to respond to TNFalpha and IL-1beta in functional assays. Sp1- and AP-1 binding sites lying in proximity to the NF-kappaB site do not seem to play a major role for cytokine responsiveness. Finally, cotransfection experiments with expression vectors validate that the natural promoter contains a functional NF-kappaB site.
 ...
PMID:Characterization of the promoter for the human long pentraxin PTX3. Role of NF-kappaB in tumor necrosis factor-alpha and interleukin-1beta regulation. 907 34

Leptin, an adipocyte-secreted hormone, is one of the central regulators of body weight homeostasis. In humans and rodents, two major forms of leptin receptors (OB-R) are expressed. The short form (OB-RS), considered to lack signaling capability, is detected in many organs. In contrast, OB-R long form (OB-RL) predominates in the hypothalamus, but is also present at low levels in peripheral tissues. Transient transfection experiments have demonstrated that OB-RL transduces an intracellular signaling similar to interleukin (IL)-6 type-cytokine receptors. To define the specificity by which OB-R induces genes and cooperates with signal transduction pathways utilized by other hormones and cytokines, rat and human hepatoma cell lines were generated which stably express human OB-RL. Hepatoma cell lines selected for appreciable levels of OB-RL mRNA display enhanced leptin binding and responded to leptin with an IL-6 receptor-like signaling that includes the activation of STAT proteins, induction of acute-phase plasma proteins, and synergism with IL-1 and tumor necrosis factor-alpha. A leptin-mediated recruitment of phosphatidylinositol 3-kinase to insulin receptor substrate-2 was also detected. However, no significant tyrosine phosphorylation of insulin receptor substrate-2 and modulation of the immediate cell response to insulin were observed. The data suggest that OB-RL action in hepatic cells is equivalent to that of IL-6 receptor. However, leptin does not play a specific role in muting insulin action on hepatoma cells and therefore may not contribute to the diabetic symptoms associated with obesity.
 ...
PMID:Leptin receptor action in hepatic cells. 919 22

ONO-4007 is a new synthetic lipid A derivative with low endotoxic activities. We have examined the therapeutic effects of ONO-4007 on rat hepatocellular carcinoma KDH-8 cells, rat fibrosarcoma KMT-17 cells and rat mammary adenocarcinoma SST-2 cells in vivo. Multiple systemic i.v. administration of ONO-4007 was performed on days 7, 14 and 21 after tumor implantation of KDH-8 and SST-2 cells, and on days 5, 10 and 15 after tumor implantation of KMT-17 cells. ONO-4007 showed significant therapeutic effects on KDH-8 cells; by the administration of ONO-4007 (2.5 mg/kg) 70% of rats were cured and by the administration of ONO-4007 (5 mg/kg) 50% of rats were cured. Furthermore, the ONO-4007 treatment prolonged the mean survival time of KDH-8-bearing rats. However, ONO-4007 had no effect on KMT-17 and SST-2 cells, and it had no direct effect on the growth of KDH-8 cells in vivo. Albeit the stimulation with ONO-4007 induced mRNA expressions of interleukin (IL)-1alpha, IL-6 and tumor necrosis factor (TNF)-a, those of IL-2, IL-4, IL-10 and interferon (IFN)-gamma were not induced. Using a bioassay, we found that the production of TNF-alpha in the tumor tissues was induced by ONO-4007 in a dose-dependent manner. KDH-8 cells were sensitive to human natural TNF-alpha in vitro. However, KMT-17 and SST-2 cells were resistant against TNF-alpha in vitro. These results suggest that ONO-4007 is therapeutically useful for the treatment of TNF-alpha-sensitive tumors.
 ...
PMID:A new synthetic lipid A analog, ONO-4007, stimulates the production of tumor necrosis factor-alpha in tumor tissues, resulting in the rejection of transplanted rat hepatoma cells. 921 14

We earlier demonstrated that 50% of the lethal dose of lipopolysaccharide (LPS) from Pantoea agglomerans given by the intradermal (i.d.) route is about 300 times greater than that given by the intravenous (i.v.) route, and that 400 micrograms/kg of LPS administered i.d. significantly suppressed metastasis whereas administered i.v., it did not. To learn the specific mechanism involved in this i.d. administration, the fate of LPS at the skin following administration and the concurrent production of endogenous tumor necrosis factor (TNF) in serum was examined. Histological observation following the i.d. administration of LPS (40 micrograms/kg) revealed neutrophiles in the skin 6 hours later. After 24 or 48 hours inflammatory cells were assembled at the site of injection. Endogenous TNF activity was found in the skin 24 hours after the injection and was significantly detectable even after 48 hours. Endogenous TNF was induced around tumor lesions of Meth A fibrosarcoma, MH134 hepatoma and Lewis lung carcinoma by treatment of LPS administered i.d. Taken together, these findings suggest that the antitumor activity of i.d. administered LPS results from the continuous supply of a small amount of this substance producing free TNF and activating inflammatory cells such as macrophages having membrane bound proTNF on their surface from the injected site to the tumor lesion for more than 48 hours.
 ...
PMID:Antitumor mechanism of intradermal administration of lipopolysaccharide. 921 52


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>