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)

Mammalian cells become more susceptible to radiation-induced death and mutagenesis when restricted in their production of the natural polyamines putrescine, spermidine and spermine. The effects of polyamine deprivation are reversed by N-(2-mercaptoethyl)-1, 3-diaminopropane (WR1065), a simple aminothiol that has been extensively studied for its radioprotectant properties. Because this compound and its oxidized derivative WR33278 bear some resemblance to the polyamines, it was hypothesized that radioprotection by WR1065 or its metabolites is derived, at least in part, from their ability to supplement the natural polyamines. To evaluate the ability of these aminothiol compounds to emulate polyamine function in intact cells, rat liver hepatoma (HTC) cells were treated with radioprotective doses of WR1065; the ability of this compound to affect various aspects of normal polyamine metabolism was monitored. Although cellular WR1065 was maintained at levels exceeding those of the polyamines, this aminothiol did not have any polyamine-like effect on the initial polyamine biosynthetic enzyme, ornithine decarboxylase, or on polyamine degradative reactions. On the contrary, treatment with relatively low levels of WR1065 resulted in an unexpected increase in putrescine and spermidine synthesis. WR1065 treatment enhanced the stability, and consequently the activity, of ornithine decarboxylase. This stabilization seems to result from a WR1065-induced delay in the synthesis of antizyme, a critical regulatory protein required in the feedback modulation of polyamine synthesis and transport. The increase in cellular spermidine induced by WR1065 might explain its antimutagenic properties, but is probably not a factor in protection against cell killing by radiation. This is the first evidence that compounds can be designed to control polyamine levels by targeting the activity of the regulatory protein antizyme.
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PMID:Mammalian cell polyamine homeostasis is altered by the radioprotector WR1065. 976 31

We investigated polyamine metabolism in hepatocellular carcinoma (HCC) with respect to tumor volume doubling time, degree of differentiation, and prevalence of portal invasion and intrahepatic metastasis. Ornithine decarboxylase (ODC) activity and the spermidine/spermine ratio were correlated with tumor volume doubling time. ODC activity was higher in moderately and poorly differentiated HCC than in well-differentiated HCC. The prevalence of portal invasion and intrehapatic metastasis was higher in patients with high ODC activities. We conclude that polyamine metabolism in HCC estimates the degree of malignancy.
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PMID:Relationship of polyamine metabolism to degree of malignancy of human hepatocellular carcinoma. 976 73

The tumor suppressor Bin1 was identified through its interaction with the N-terminal region of Myc which harbors its transcriptional activation domain. Here we show that Bin1 and Myc physically and functionally associate in cells and that Bin1 inhibits cell proliferation through both Myc-dependent and Myc-independent mechanisms. Bin1 specifically inhibited transactivation by Myc as assayed from artificial promoters or from the Myc target genes ornithine decarboxylase (ODC) and alpha prothymosin (pT). Inhibition of ODC but not pT required the presence of the Myc binding domain (MBD) of Bin1 suggesting two mechanisms of action. Consistent with this possibility, a non-MBD region of Bin1 was sufficient to recruit a repression function to DNA that was unrelated to histone deacetylase. Regions outside the MBD required for growth inhibition were mapped in Ras cotransformation or HepG2 hepatoma cell growth assays. Bin1 required the N-terminal BAR domain to suppress focus formation by Myc whereas the C-terminal U1 and SH3 domains were required to inhibit adenovirus E1A or mutant p53, respectively. All three domains contributed to Bin1 suppression of tumor cell growth but BAR-C was most crucial. These findings supported functional interaction between Myc and Bin1 in cells and indicated that Bin1 could inhibit malignant cell growth through multiple mechanisms.
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PMID:Bin1 functionally interacts with Myc and inhibits cell proliferation via multiple mechanisms. 1038 Aug 78

Hepatocyte growth factor (HGF) exerts a cytostatic effect on HepG2 and B16-F1 cell lines. To evaluate the possible involvement of the apoptotic process in this effect, we performed studies at cellular and molecular levels. HGF induced apoptosis only in HepG2 hepatoma cells at day 3 in about 20% of the cells undergoing growth inhibition, while hallmarks of apoptosis did not occur in B16-F1 melanoma cells. During the first 24 h after HGF treatment, enhanced expression of the pro-apoptotic genes bax and c-Myc was observed at level of mRNA and protein. Concomitant induction of antizyme (AZ) might lower ornithine decarboxylase (ODC) protein level though a huge increase in ODC mRNA level took place. This was suggested as a signal for apoptosis decisional phase. The levels of the proteins examined except that of AZ fell down thereafter when HepG2 cells underwent apoptosis. In B16-F1 cells, only ODC and AZ protein levels were elevated probably in relation to the initial elevated growth rate and the absence of apoptosis involvement in the following cytostatic effect of HGF in melanoma cells. Consistent with this hypothesis, bax mRNA and protein levels were unchanged or even lower relative to control values.
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PMID:Hepatocyte growth factor induces pro-apoptotic genes in HepG2 hepatoma but not in B16-F1 melanoma cells. 1116 78

The inbred DRH rats are highly resistant to the induction of hepatocellular carcinoma (HCC) by feeding of 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB). Previously, we found that two quantitative trait loci (QTLs), Drh1 and Drh2, significantly reduced the number, size and area of glutathione S-transferase-placental form (GST-P)-positive foci and GST-P mRNA levels in (F344xDRH)F(2) rat livers induced by feeding 3'-Me-DAB for 8 weeks. It is unclear, however, whether these QTLs affecting pre-neoplastic lesions are also the determinants of the later stage hepatocarcinogenesis, and whether there are any additional QTLs affecting hepatocarcinogenesis in the progression stage. To answer these questions, we analyzed QTL parameters for liver tumors in 99 (F344xDRH)F(2) rats induced by feeding 3'-Me-DAB for 20 weeks. The QTL parameters examined were GST-P mRNA, ornithine decarboxylase activity, and the number and total area of HCC/nodules macroscopically detectable on the liver surface. In composite interval mapping, we observed two major QTL peaks overlapping on the map positions of Drh1 on rat chromosome 1 (RNO1) and Drh2 on RNO4, respectively. The newly mapped QTL on RNO1 affected the GST-P mRNA level at 20 weeks of 3'-Me-DAB feeding, but did not affect the number and size of tumors. The primary effect of Drh1 is, therefore, to inhibit GST-P induction and to prevent enzyme altered foci (EAF) formation. On the other hand, the QTLs on RNO4, co-mapped to Drh2, affected all parameters of liver tumors examined except for the level of GST-P mRNA. The latter QTLs influenced not only the induction of GST-P and formation of EAF but also the progression of tumors in the later stage of hepatocarcinogenesis. The GST-P induction is differentially controlled by stages of hepatocarcinogenesis and the DRH resistance to carcinogenesis is principally attributed to the QTLs on RNO4 out of two resistance QTLs identified in the pre-neoplastic stage.
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PMID:Resistance of DRH strain rats to chemical carcinogenesis of liver: genetic analysis of later progression stage. 1175 40

Ornithine decarboxylase (ODC), a critical regulatory enzyme for polyamine biosynthesis, is strictly regulated in human cells. Several studies suggested the importance of elevated enzymatic activity and altered biochemical characteristics of ODC in malignant cells. Because mutation of ODC in primary human hepatocellular carcinoma has been reported, we examined whether the genetic alterations, such as mutations or structural alterations of the gene, also account for the alteration of ODC activity in human colorectal cancer. No mutation or structural alteration in the ODC was detected in any of the colorectal tumors and normal tissues examined. These results suggest that a mutation or structural alteration of the ODC may not be involved in human colorectal carcinogenesis.
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PMID:Genetic alterations of the ornithine decarboxylase gene in human colorectal cancers. 1214 77

Identification and use of effective cancer chemopreventive agents have become an important issue in public health-related research. For identification of potential cancer chemopreventive constituents we have set up a battery of cell- and enzyme-based in vitro marker systems relevant for prevention of carcinogenesis in vivo. These systems include modulation of drug metabolism (inhibition of Cyp1A activity, induction of NAD(P)H:quinone reductase (QR) activity in Hepa1c1c7 murine hepatoma cell culture), determination of radical scavenging (DPPH scavenging) and antioxidant effects (scavenging of superoxide anion-, hydroxyl- and peroxyl-radicals), anti-inflammatory mechanisms (inhibition of lipopolysaccharide (LPS)-mediated nitric oxide (NO) generation by inducible NO synthase (iNOS) in Raw 264.7 murine macrophages, cyclooxygenase-1 (Cox-1) inhibition), and anti-tumor promoting activities (inhibition of phorbol ester-induced ornithine decarboxylase (ODC) activity in 308 murine keratinocytes). We have tested a series of known chemopreventive substances belonging to several structural classes as reference compounds for the identification of novel chemopreventive agents or mechanisms. These include organosulfur compounds (phenethylisothiocyanate (PEITC), diallylsulfide, diallyldisulfide), terpenes (limonene, perillyl alcohol, oleanolic acid, 18-beta-glycyrrhetinic acid), short-chain fatty acids (sodium butyrate), indoles (indole-3-carbinol), isoflavonoids (quercetin, silymarin, genistein), catechins ((-)-epigallocatechin gallate (EGCG)), simple phenols (ellagic acid, resveratrol, piceatannol, curcumin), pharmaceutical agents (piroxicam, acetylsalicylic acid, tamoxifen), and vitamins/derivatives (ascorbic acid, Trolox). We confirmed known chemopreventive mechanisms of these compounds. Additionally, we could demonstrate the usefulness of our approach by identification of hitherto unknown mechanisms of selected agents. As an example, we detected anti-inflammatory properties of PEITC, based on NF-kappaB-mediated inhibition of NO production. Further, PEITC inhibited phorbol ester-induced superoxide anion radical production in granulocytes, and ODC induction in the 308 cell line. These mechanisms might contribute to the chemopreventive potential of PEITC.
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PMID:Mechanism-based in vitro screening of potential cancer chemopreventive agents. 1262 14

Two isoforms of cyclooxygenase (COX) participate in growth control; COX-1 is constitutively expressed in most cells, and COX-2 is an inducible enzyme in response to cellular stimuli. An induction of COX-2 found in neoplastic tissues results in increased cell growth, inhibition of apoptosis, activation of angiogenesis, and decreased immune responsiveness. Although both COX-1 and COX-2 inhibitors are suppressors of cell proliferation and appear to be chemopreventive agents for tumorigenesis, the molecular mechanisms mediating antiproliferative effect of COX inhibitors are still not well defined. This study contrasts and compares the effects of aspirin and celecoxib, inhibitors of COX-1 and COX-2, in rat hepatoma HTC-IR cells. The following were assessed: cell proliferation and apoptosis, ornithine decarboxylase (ODC) activity, and pattern expression of three immediate-early genes, c-myc, Egr-1, and c-fos. We have shown that the treatment of hepatocytes in vitro with the selective COX-2 inhibitor, celecoxib, was associated with induction of apoptosis and complete inhibition of cellular proliferation. Aspirin exhibited a small antiproliferative effect that was not associated with apoptosis. Treatment with celecoxib produced dose- and time-dependent decrease in ODC activity. In addition, at higher drug concentration the decrease in ODC activity was greater in proliferating than in resting cells. Much lesser inhibitory effect on ODC activity was observed in aspirin-treated cells. The two COX inhibitors did not change c-myc expression, significantly decreased the expression of Egr-1, and differentially altered expression of c-fos; aspirin did not change, but celecoxib dramatically decreased the levels of c-fos-mRNA. Our study revealed that celecoxib and aspirin share the ability to inhibit ODC activity and alter the pattern of immediate-early gene expression. It seems that some of the observed effects are likely to be related to COX-independent pathways. The precise mechanisms of action of COX inhibitors should be defined before using these drugs for cancer chemopreventive therapy.
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PMID:Do altering in ornithine decarboxylase activity and gene expression contribute to antiproliferative properties of COX inhibitors? 1267 17

Two hepatocarcinoma cell lines, the Hepa-1 wild-type (c1c7) and the beta-subunit mutated (c4) lacking hypoxia-inducible factor-1 (HIF-1) activity, were differentially susceptible to apoptosis by hepatocyte growth factor (HGF). The c4 cells were 40% apoptotic 48 h after HGF treatment. On the contrary, the wild-type c1c7 cells showed modest signs of apoptosis only at 72 h. The revertant vT[2] cells, consisting of c4 cells stably transfected with HIF-1beta expression vector, behaved as the parental cells. To understand the mechanisms of this different sensitivity, we examined a panel of genes involved in apoptosis: ornithine decarboxylase, c-Myc and p53 protein levels progressively decreased while JNK1, caspase 8 and 3 activities persistently increased in c4 cells undergoing apoptosis. Distinct time-related events in c1c7 cells were the transient activations of JNK1 and caspase 8 followed by the accumulation of ODC and c-Myc proteins. The proapoptotic effect of HGF in c4 hepatocarcinoma cells seems to be related to HIF-1 deficiency with loss of cytoprotective and signalling functions. This may contribute to the triggering of the extrinsic pathway consisting in caspase 8 activation, which in turn causes BID cleavage and cytochrome c release. The effector caspase 3 is also activated.
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PMID:Hepatocyte growth factor induces apoptosis through the extrinsic pathway in hepatoma cells: favouring role of hypoxia-inducible factor-1 deficiency. 1282 40

The antitumor effects of melatonin on diethylnitrosamine (DEN)-initiated and/or phenobarbital (PB)-promoted hepatocarcinogenesis were investigated in male F344 rats. Five-week-old male F344 rats were divided into eight groups. Rats in groups 1-5 were given DEN (100 mg/kg body weight, i.p.) once a week for 3 wk, whereas those in groups 6-8 received vehicle treatment. Groups 1-3 and 7 were given 500 ppm PB in drinking water for 20 wk after DEN or vehicle treatment. Group 2 was given 400 ppm melatonin-containing diet during the initiation phase. Groups 3 and 5 were fed melatonin-containing diet for 20 wk, starting 1 wk after the last dosing of DEN. Group 6 was given melatonin-containing diet alone throughout the experiment (24 wk). Group 8 was treated with vehicle alone. Liver neoplasms were recognized only in DEN-treated groups. The incidences and multiplicities of hepatocellular adenoma and hepatocellular carcinoma (HCC) in group 3 were significantly smaller when compared with group 1 (P < 0.001 or P < 0.002). The average and unit areas of glutathione S-transferase placental form (GST-P)-positive foci of groups 2 and 3 were significantly smaller than those of group 1 (P < 0.001 or P < 0.01). The density and average area of these preneoplastic lesions of group 5 were also smaller than those of group 4 (P < 0.001 or P < 0.005). In addition, the ornithine decarboxylase activity in nonneoplastic liver tissue was reduced by melatonin treatment in both the initiation and postinitiation phases. These results suggest that melatonin has an antitumor-promoting ability in DEN-initiated and PB-promoted hepatocarcinogenesis in rats.
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PMID:Chemopreventive effects of melatonin on diethylnitrosamine and phenobarbital-induced hepatocarcinogenesis in male F344 rats. 1508 67


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