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)

1. A systematic study is reported on the control of 1-phosphatidylinositol 4-kinase (PI kinase) and PI 4-phosphate 5-kinase (PIP kinase), enzymes of the phosphatidylinositol phosphorylation pathway which leads to the production of second messengers. IP3 and DAG. In liver of normal male, adult, fed Wistar rats the steady state activity of PI kinase was 0.5 +/- 0.01 and that of PIP kinase was 0.046 +/- 0.003 nmol/hr/mg protein. The concentration of IP3 was 1.8 +/- 0.1 pmol/mg protein. 2. That the two kinases have short half-lives was observed in starvation. where in the rat liver or bone marrow activities rapidly decreased and on refeeding were restored in a day. Injection to rats of the protein synthetic inhibitor, cycloheximide, yielded t1/2 = 80 min for the two enzymes in bone marrow and t1/2 = 80 min in liver. 3. Linkage of the signal transduction enzymes with proliferation was shown by the high activities as compared to liver of these enzymes in rat organs of high cell renewal capacity, e.g., thymus, bone marrow, spleen and testes. 4. Linkage with malignant proliferation was indicated by the observation that in rat hepatomas the enzyme activities increased 5- to 9-fold and were highest in rapidly growing hepatoma 3924A (29- and 45-fold). 5. In human primary ovarian carcinoma PI and PIP kinase activities were elevated 4.4 and 2.9-fold, respectively, and in OVCAR-5 cells, 32- and 11-fold, respectively. Similar increases were observed in MDA-MB-435 human breast carcinoma cells in comparison with normal breast parenchymal cells. 6. The linkage of signal transduction enzyme activities with malignant proliferation was also observed in experiments when human breast carcinoma cells were plated in flasks and expressed their proliferative capacity in the log phase. PI and PIP kinase activities steadily and coordinately increased to a peak 11-fold rise in mid-log phase. In late log and plateau phases the kinase activities gradually declined to the starting level. Similar observations were made for the two enzymes in human ovarian carcinoma OVCAR-5 cells and in rat hepatoma 3924A cells in tissue culture. 7. In animals injected with cycloheximide the bone marrow PI and PIP kinase activities exhibited t1/2 = 0.12 hr, the shortest decay rate in comparison with 8 enzymes of purine and pyrimidine biosynthesis with t1/2 = 0.6 to 4.3 hr. 8. Injection of tiazofurin decreased PI and PIP kinase activities in the bone marrow with t1/2 = 82 and 78 min, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of signal transduction. 757 37

The activity of PIP kinase (1-phosphatidylinositol 4-phosphate 5-kinase; EC 2.7.1.68), the second ATP-utilizing enzyme of 1,4,5-trisphosphate and diacylglycerol biosynthesis, was determined in the rat in a spectrum of transplantable solid hepatomas of different growth rates and in normal tissues of high and low cell renewal rates. In a standard isotopic method developed for the assay, the enzyme activity was linear with time for 4 min and proportional with protein concentration over a range of 0.05 to 1 mg per 0.135-ml reaction mixture. The apparent Km for the substrate PIP (phosphatidylinositol 4-phosphate) and for ATP and Mg2+ in normal liver were 0.06, 0.5, and 4.2 mM, respectively, and in rapidly growing hepatoma 3924A, 0.08, 0.7, and 7.1 mM. The kinase activity in adult Wistar rat liver was 0.046 +/- 0.003 nmol/h/mg protein. In hepatomas of slow and intermediate growth rates, PIP kinase activity increased 3.3-9.7-fold, and in hepatoma 3924A, it was elevated 45-fold over that of normal liver. When hepatoma 3924A cells were plated and expressed their proliferative program, enzyme activity increased 4.3-fold in mid-log phase. To further clarify the linkage between PIP kinase activity and proliferation, enzyme activity was determined in rat organs of high and low cell renewal capacity. The PIP kinase activity in rat thymus, bone marrow, spleen, and testes was 5.4-, 6.3-, 4.8- and 4.3-fold higher, respectively, than in normal rat liver; in lung, brain, skeletal muscle, renal cortex, and heart, the activities were low. In all tissues examined, the activity of PIP kinase was 4.6 to 18% of that of phosphatidylinositol kinase. Since enzymes of crucial significance frequently have short half-lives, the decay rates of PIP kinase were examined in liver, bone marrow, and hepatoma 3924A in rats injected with cycloheximide, which inhibits protein biosynthesis. In cycloheximide-treated animals, PIP kinase had the shortest decay rate (t1/2 = 0.12 h) in comparison with eight enzymes of purine and pyrimidine biosynthesis of rat bone marrow (t1/2 = 0.6 to 4.3 h). In liver and solid hepatoma 3924A, the activity of PIP kinase was degraded less rapidly (t1/2 = 5 h). The relationship of PIP kinase activity with proliferation and transformation is apparent in the high activity in thymus, bone marrow, spleen, and testes and in the increased activities in the rat hepatomas of different growth rates. The coordinate increases in phosphatidylinositol and PIP kinase activities suggest that the capacity for signal transduction is heightened in cancer cells.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:1-Phosphatidylinositol 4-phosphate 5-kinase (EC 2.7.1.68): a proliferation- and malignancy-linked signal transduction enzyme. 792 99

The purpose of this study was to elucidate the behavior of signal transduction activity in rat and human carcinoma cells. Signal transduction activity was measured by the steady-state activity of the three enzymes involved in the conversion of 1-phosphatidylinositol (PI) to IP3, PI 4-kinase, PI 4-phosphate 5-kinase, and phospholipase C activities were measured by our methods. The results indicate that the steady-state activities of the three signal transduction enzymes and the end-product, IP3, were up-regulated in a transformation- and progression-linked fashion. In rat liver PI kinase, PIP kinase and PLC activities were 0.4, O.04, and 800 nmol/hour/mg protein, respectively. PI and PIP kinase and PLC activities were increased 2- to 8-fold in five rat hepatomas and 29-, 45-, and 4-fold, respectively, in rapidly growing hepatoma 3924A. PI and PIP kinase activities as compared to normal ovary were elevated in human ovarian epithelial carcinomas (4- and 3-fold) and in OVCAR-5 cells in culture (31- and 11-fold). Compared to normal breast parenchymal cells, PI and PIP kinase activities were increased in human breast carcinoma cells (96- and 16-fold). When breast carcinoma cells were plated and expressed their neoplastic proliferative program. IP3 concentration increased 20-fold in early log phase: PI and PIP kinase activities increased 11-fold in mid log phase: PLC activity did not change throughout. PI and PIP kinase activities in bone marrow had short half-lives (t1/2 = 8 minutes) but PLC had a long one (t1/2 > 6 hours). The elevated signal transduction activity was down-regulated by the anti-cancer drug, tiazofurin, and also by quercetin, an inhibitor of PI kinase. The addition of these drugs to cultured carcinoma cells reduced the IP3 concentration, and the cells were killed. These integrated studies are the first showing that signal transduction activity is stringently linked with transformation and progression in rat and human solid tumors and carcinoma cells. Down-regulation (by tiazofurin) or inhibition of PI and PIP kinase activities (by quercetin) in human carcinoma cells led to a marked reduction of IP3 concentration and to cell death. Tiazofurin and quercetin may be useful in the treatment of carcinomas with increased signal transduction capacity.
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PMID:Increased signal transduction activity and down-regulation in human cancer cells. 904

Evidence for heightened capacity for signal transduction in rat hepatoma as well as in human breast and ovarian carcinoma cells as reflected by coordinate increases in PI kinase and PIP kinase in the PI phosphorylation sequence leading to the production of second messengers IP3 and DAG is shown. The linkage of signal transduction enzymes with malignant growth is also seen as MDA-MB- 435 human breast carcinoma or ovarian OVCAR-5 cells express their proliferative capacity in tissue culture in the log phase. In both cases, quercetin inhibit cell proliferation with a decline in PI kinase activity and IP3 levels preceding the growth inhibition seen with quercetin. The elevated steady state activities of PI and PIP kinase indicate a metabolic up-regulation in signal transduction capacity of cancer cells which is down-regulated by quercetin. Since the gain in function manifested in the over-expressed capacity for signal transduction confers selective growth advantage to cancer cells, increased activities of PI and PIP kinases may be considered as sensitive targets for cancer chemotherapy. The potential of quercetin as an interceptor of intracellular signal transduction mechanisms needs to be explored.
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PMID:Intracellular signalling: phosphatidylinositol lipid metabolism in cancer cells. 934 25

The purpose of this paper was to clarify critical aspects of the behavior of signal transduction activity in normal and cancer cells. 1. Signal transduction activity in the conversion of phosphatidylinositol through PI and PIP kinases and PLC to IP3 is regulated at multiple sites. In liver, hepatomas and human carcinomas PIP kinase is the rate limiting enzyme and PLC activity is present in great excess. 2. The steady-state signal transduction activity as measured by the three enzyme activities and IP3 concentration was markedly up-regulated in rat hepatomas of different growth rates. The steady-state specific activities of the three signal transduction enzymes were elevated in ovarian carcinomas as compared to normal ovary. Increased enzyme activities were also observed in human breast carcinoma cells as compared to normal human breast parenchymal cells. In breast, ovarian and rat hepatoma cells as they go through lag, log and plateau phases, IP3 concentration in the early lag phase increased 4.5- to 20-fold and PI and PIP kinase activities peaked in mid-log phase. These events returned to baseline levels in the plateau phase. PLC activity did not change. 3. The bone marrow PI and PIP kinase activities in 3-day starvation were decreased to 13% and IP3 concentration was reduced to 24%; at 1-day refeeding they returned to normal. PLC activity changed little. These alterations are in line with the rapid t1/2 degradation rates (12 min) of PI and PIP kinases observed in studies with cycloheximide. By contrast, PLC has a long half-life. 4. The molecular action of tiazofurin entails inhibition of IMP DH activity, decrease in GTP and IP3 concentrations, reduction of ras and myc oncogene expression, and signal transduction enzyme activities. These events are followed by induced differentiation and apoptosis. There are also decreases in enzyme activities which have rapid turnover, including TdR kinase, dTMP synthase, and GPRT. In vitro studies indicated that these events are abrogated by addition of guanine which restores GTP concentrations. Therefore, most or all these events were brought about by the reduced GTP concentration in the tiazofurin target cells. 5. Quercetin and genistein are able to inhibit PI and PIP kinase activities and reduce IP3 concentration in vivo and in tissue culture systems. These flavonoids are also inhibitors of cell proliferation and clonogenic ability in rat hepatoma 3924A and in human OVCAR-5 and MDA-MB-435 cells. Quercetin down-regulated the expression of c-myc and Ki-ras oncogenes and led to induced differentiation and apoptosis in K562 cells. Genistein reduced IP3 concentration in vivo and in the tissue culture system. Genistein is antiproliferative and has cytototoxicity in human carcinoma cells. All three drugs, tiazofurin, quercetin and genistein, act, in part at least, through depression of cellular IP3 concentration although the mechanisms may not be identical. 6. Quercetin and genistein, which attack different targets and different phases of the cell cycle, proved to be synergistic in OVCAR-5 cells. The impact of tiazofurin, genistein and quercetin is of interest because the drugs crucially inhibit the display of the neoplastic program of cells and lead to induced differentiation and apoptosis.
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PMID:Regulation of the signal transduction program by drugs. 938 80

Recent work in this Laboratory showed increased activity of PI 4-kinase, PIP kinase and PLC in various cancer cells, indicating a stepped-up capacity for signal transduction. This elevated potential was paralleled with increased concentration of the end product of signal transduction, IP3. Current investigations showed that in normal cells the activities of the specific phosphatases (which degrade PIP2 and PIP and oppose those of the synthetic enzymes) were 4 to 5 orders of magnitude higher than those of the synthetic kinases. In hepatoma cells the specific phosphatase activities markedly decreased. Thus, in cancer cells the marked elevations in activities of the synthetic enzymes were opposed by a reduction in the activities of the degradative specific phosphatases. This enzymic imbalance is responsible, in part at least, for the elevated capacity of signal transduction and IP3 concentration. Since the enzymic activities measured were proportionate with time elapsed and amount of enzyme added, the alterations in activities should reflect changes in enzyme amounts. These alterations indicate a reprogramming of gene expression which should confer selective advantages to the cancer cells, marking out the elevated synthetic enzyme activities as potentially sensitive targets for drug treatment. We showed earlier that tiazofurin, which curtailed the biosynthesis of enzymes with short half-lives such as PI and PIP kinases, down-regulated signal transduction and brought down IP3 concentration. Quercetin and genistein chiefly inhibited PI-4 kinase and PIP kinase, respectively, and as a result reduced IP3 concentration in cancer cells. Current studies reveal that tiazofurin with quercetin, tiazofurin with genistein, and quercetin with genistein were synergistic in killing human cancer cells and in reducing signal transduction activity. In estrogen receptor-negative MDA-MB-435 human breast carcinoma cells which have elevated signal transduction activity, tamoxifen caused IC50S for growth inhibition and cytotoxicity of 12 and 0.7 microM, respectively. When tiazofurin was added to breast carcinoma cells, followed 12 hr later by tamoxifen, synergism was observed in growth inhibition, in clonogenic assays and in the reduction of IP3 concentration. The synergistic action of tiazofurin and tamoxifen and the other synergistic drug interactions outlined above may have implications in the clinical treatment of neoplasias.
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PMID:Amplification of signal transduction capacity and down-regulation by drugs. 1047 Mar 66