Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Treatment of M5076 tumor cells with the phorbol estes 12-O-tetradecanoylphorbol 13-acetate (TPA) and phorbol 12,13 dibutyrate (PdBu) inhibited cellular proliferation, whereas 1,2-dioctanoyl-glycerol (DiC8) and 1-oleoyl2-acetyl-glycerol (OAG) did not affect cell growth. Inhibition of cellular proliferation in this cell line appears to be a consequence of protein kinase C (PKC) down-regulation since phorbol esters, but not a single application of diacylglycerols (DGs) down-regulated cellular PKC levels. By repeated application of DGs, PKC down-regulation was achieved and correlated with inhibition of proliferation. Phorbol ester-induced PKC down-regulation was reversible, upon removal of the phorbol ester, and the reappearance of PKC was associated with resumption of proliferation. The mitogenic responsiveness of these cells to added serum depended upon cellular PKC levels. Phorbol esters also caused the phosphorylation of two proteins which were not phosphorylated in response to DG treatment. Inhibition of growth of M5076 cells appears to be associated with phosphorylation of two novel proteins and/or PKC down-regulation.
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PMID:Protein kinase C levels and protein phosphorylation associated with inhibition of proliferation in a murine macrophage tumor. 231 12

We studied the effects of epidermal growth factor (EGF), 12-O-tetradecanoylphorbol-13-acetate (TPA), and 1-oleoyl-2-acetyl-glycerol (OAG) on cytoplasmic pH (pHi) and cell growth in cultured porcine thyroid cells. pHi was measured using 2',7'-bis(2-carboxyethyl-5,6-carboxyfluorescein (BCECF), an internalized fluorescent pH indicator. EGF, TPA, and OAG alkalinized the thyroid cells and stimulated their growth. These EGF-, TPA-, and OAG-stimulated cell alkalinization and growth depended on extracellular Na concentrations and were inhibited by amiloride, an inhibitor of Na(+)-H+ exchanger, indicating that EGF-, TPA-, and OAG-stimulated cell alkalinization and growth may occur through activation of Na(+)-H+ exchange. Alkalinization seems to be involved in thyroid cell growth. TPA (a tumor-promoting phorbol ester) and OAG (synthetic diacylglycerol), both potent activators of protein kinase C, imitate the action of EGF in rapidly elevating pHi and stimulating cell growth in thyroid cells. Trifluoperazine, an inhibitor of protein kinase C, inhibited EGF-, TPA-, and OAG-stimulated cell alkalinization and growth. The data suggest that activation of protein kinase C may be involved in the mechanism of EGF-stimulated cell alkalinization and growth of the thyroid cells.
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PMID:Stimulation of porcine thyroid cell alkalinization and growth by EGF, phorbol ester, and diacylglycerol. 231 41

The involvement of Ca2+ and PGE1 in myoblast fusion has been well documented. Extracellular Ca2+ is essential for myoblast adhesion, alignment, and fusion. There is an obligatory increase in Ca2+ influx immediately preceding fusion and the Ca2+ ionophore A23187 promotes precocious fusion. PGE1 receptors appear just prior to fusion, and an antagonist of PGE1 binding to cell surface receptors blocks fusion when added prior to Ca2+ influx. Finally, exogenous PGE1 induces precocious fusion. The present study was an initial test of the hypothesis that membrane protein phosphorylation by protein kinase C (PKC) links PGE1 receptor occupancy and the increase in Ca2+ influx. Our conclusion that PKC is an essential component in the regulation of myoblast fusion is based in part on the following evidence: (1) an activator of PKC, the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), at low concentration and for a brief exposure period, induces precocious fusion and stimulates Ca2+ influx; (2) 4 alpha-phorbol-12,13-didecanoate, an inactive analog of TPA, has no discernible effect on fusion or Ca2+ influx; (3) 1-oleoyl-2-acetyl glycerol, an analog of endogenous diacylglycerol (DAG) which activates PKC, promotes precocious fusion, as does the DAG kinase inhibitor R59022 (6-[2-[4-[(4-fluorophenyl)phenylmethylene]-1-piperidinyl]ethyl]-7- methyl-5H-thiazole-[3,2 alpha]-pyrimidin-5-one) which raises the level of endogenous DAG by inhibiting its catabolism; (4) 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), a highly potent PKC inhibitor, reversibly blocks myogenesis at a point between alignment and fusion; and (5) H-7 also blocks the normal increase in Ca2+ influx preceding fusion.
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PMID:Role of protein kinase C in chick embryo skeletal myoblast fusion. 232 43

The time course of plasma substrate level alterations in the tumor-bearing (TB) host and their relationship to tumor burden or weight loss has not been well defined. Plasma glucose, lactate, pyruvate, cholesterol, triglycerides, acetoacetate, beta-hydroxy butyrate, and glycerol levels were measured in postabsorptive TB and nontumor-bearing (NTB) male Fisher 344 rats at weekly intervals for 5 weeks. Chronically starved rts (CS) had plasma substrates measured at Week 3 and compared with TB and NTB levels. Tumor burden was 0.5% of body weight at Week 1, 3.5% at Week 2, 12% at Week 3, and 20% at Week 5. Glucose levels were significantly lower in TB versus NTB (P = 0.01) at Week 1 and progressively declined in TB versus NTB through Week 5 (P less than 0.001). At Week 2, plasma triglycerides, cholesterol, acetoacetate, and beta-hydroxy butyrate were significantly elevated in TB versus NTB (P less than 0.001) and increased further to Week 5. The profile of substrate changes in TB and CS, when compared to NTB rats at Week 3, were different, suggesting that the plasma substrate alterations seen in the TB state were not secondary to starvation. In addition, when tumors were excised from TB animals at Week 3 and plasma substrates were determined 1 week later, all substrates that were different between TB and NTB animals, except cholesterol, returned to NTB levels when compared to sham-operated controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Substrate alterations in a sarcoma-bearing rat model: effect of tumor growth and resection. 235 23

The purpose of this study was to evaluate whether heart glucose metabolism can account for elevated heart oxygen consumption in a tumor-bearing host. This is the first report of altered metabolism in perfused hearts from tumor-bearing animals. Glucose, glycerol, lactate, and amino acid metabolism was examined under steady-state conditions in isolated perfused hearts from sarcoma-bearing rats and compared to the metabolism in hearts from starved (96 hr) and fed control rats. Heart dry weight was reduced by 10% in tumor-bearing rats and by 30% in starved rats when compared to freely fed control animals. Cardiac glucose uptake was decreased in tumor-bearing rats (206 +/- 33 mumoles/hr/g dry wt) compared to both starved (298 +/- 18) and fed control rats (293 +/- 25). Hearts from both fed and starved controls released lactate and glycerol at significant rates during perfusion which was not evident in hearts from tumor-bearing rats. The release of individual amino acids from working hearts during perfusion was different among the animal groups with a severe depression of both glutamine and alanine release in tumor-bearing rats. In starved rats alanine release was normal although glutamine release was depressed by more than 50%. The net release of all amino acids was lowest in hearts from tumor-bearing rats, intermediate in the starved animals, and highest in the control animals, while the nonmetabolized amino acids (phenylalanine, tyrosine, methionine) were released at increased rates only from tumor-host hearts, indicating an increased net breakdown of some cardiac proteins in tumor-bearing animals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glucose uptake and amino acid metabolism in perfused hearts from tumor-bearing rats. 235 96

Altered gluconeogenesis is frequently observed in cancerous hosts. To define its derangements in the liver, we studied glucose and glycogen production in the perfused livers of tumor-bearing rats using 13C NMR spectroscopy. Nine Fischer 344 rats were inoculated with mammary adenocarcinoma. After 5 weeks, the livers were removed and perfused with Krebs buffer containing 8 mM L-[3-13C]alanine, and 13C NMR spectroscopy was performed. Nine pair-fed rats were studied as controls. The peak heights of glucose and glycogen in the 13C NMR spectra of the perfused livers and final perfusates of the two groups of rats were compared. We found comparable amounts of C1-labeled glucose and glycogen in the two groups, but C2- to C5-labeled and C6-labeled glucose and glycogen, as well as total 13C-labeled glucose and glycogen, appeared in smaller quantities in the tumor rats than in the pair-fed rats. These findings suggest that appreciable amounts of unlabeled glycerol were utilized by both groups, but less so by the tumor rats than the pair-fed rats. In addition, there was decreased production of oxaloacetate through pyruvate dehydrogenase and the Krebs cycle in the livers of the tumor rats, where the overall metabolism of alanine into glucose and glycogen was also reduced.
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PMID:Gluconeogenesis in the liver of tumor rats. 238 Dec 8

Cells from 6 of 14 different Ly-1+ murine B cell lymphomas bound to synthetic liposomes encapsulating fluorescein. The liposomes were made from distearoyl phosphatidyl choline (DSPC), distearoyl phosphatidyl glycerol (DSPG), and cholesterol. In all cases, liposome binding was due to recognition of phosphatidyl choline by the surface IgM on the tumor cells. Liposome binding could be inhibited by DSPC but not by DSPG, and the number of liposomes bound per cell was directly related to the cell surface concentration of IgM. The IgM secreted by a hybridoma derived from one of the lymphomas, CH12, was shown to agglutinate liposomes, and was used in a solid-phase immunoassay to study inhibition of liposome binding by pure phospholipids; DSPC and sphingomyelin both inhibited, whereas DSPG did not. The Ig borne by the six lymphomas that bind phosphatidylcholine also bind to both SRBC and bromelain-treated mouse erythrocytes. The idiotypic of CH12 IgM is similar to that expressed by Ly-1+ normal splenic B cells of the same specificity. The significance of these data in relation to other commonly studied autoantigens, and to the restricted specificity of normal Ly-1+ B cells is discussed.
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PMID:Phosphatidyl choline is recognized by a series of Ly-1+ murine B cell lymphomas specific for erythrocyte membranes. 241 66

The 58,000-Mr form (58K form) of the polyomavirus middle T antigen (mT) is a minor species distinguished by its phosphorylation in vivo on serine and by its efficient phosphorylation on tyrosine in immune complexes (B.S. Schaffhausen and T.L. Benjamin, J. Virol. 40:184-196, 1981). Here we report that the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, rapidly stimulates phosphorylation of this mT species when added to cultures of wild-type polyomavirus-infected or polyomavirus-transformed 3T3 cells. Incubation with TPA leads to an accumulation of the 58K mT species to levels 1.5- to 5-fold higher than that in untreated cells within 15 min. TPA specifically stimulates phosphorylation of the 58K mT species without affecting that of the 56K species. Mapping by partial proteolysis shows that TPA-stimulated phosphorylation occurs at or near the site in 58K mT that is normally phosphorylated in the absence of TPA. A synthetic diacyl glycerol, 1-oleoyl-2-acetyl-glycerol, also specifically stimulates phosphorylation of 58K mT in vivo, while an inactive phorbol analog does not. TPA fails to induce phosphorylation of a 58K mT species encoded by certain nontransforming virus mutants with altered mT proteins that normally fail to undergo phosphorylation at the 58K site. These results indicate that the 58K form of mT is phosphorylated by or through the action of protein kinase C. TPA treatment of infected cells also leads to increased levels of 58K mT as measured in the immune complex kinase reaction, in which mT becomes phosphorylated on tyrosine by pp60c-src. These results are discussed in terms of a possible role for protein kinase C in activating mT function(s), including the formation of stable complexes with pp60c-src.
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PMID:12-O-tetradecanoylphorbol-13-acetate stimulates phosphorylation of the 58,000-Mr form of polyomavirus middle T antigen in vivo: implications for a possible role of protein kinase C in middle T function. 242 91

We tested the possibility that the activation of protein kinase-C by the tumor-promoter phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) or diacylglycerol stimulates the production of prostaglandin E2 (PGE2) by the amnion. Confluent primary cultures of human amnion epithelial cells were adapted to serum-free medium and treated with the agonists for up to 8 h. Cumulative PGE2 output in the medium was measured by RIA. TPA, a potent activator of protein kinase-C, stimulated basal PGE2 output from less than 50 pg/well.5 h to 3 ng/well.5 h (P less than 0.01) in a time- and dose-dependent manner. 4-Methoxy-TPA, a weak tumor promoter derivative of TPA, was ineffective when tested in the same concentration range as TPA (1 nmol/L to 1 mumol/L). Neither calcium ionophore A23187 (20 nmol/L) nor arachidonate (1 mumol/L) stimulated PGE2 output alone, but each agonist potentiated the effect of TPA as much as 5-fold (P less than 0.01). 1,2-Dioctanoyl-sn-glycerol stimulated PGE2 output 4- to 7-fold (P less than 0.05), and this effect was potentiated by Ca ionophore and arachidonate. Studies involving actinomycin-D and cycloheximide indicated that the stimulatory effect of TPA was dependent on RNA synthesis during the first 60 min and on protein synthesis during the entire length of the phorbol ester treatment period (300 min). TPA was also able to stimulate PGE2 production after irreversible inactivation of PG endoperoxide synthase activity with acetylsalicylic acid. These results suggest that activation of protein kinase-C in amnion cells increases the de novo synthesis of the PG endoperoxide synthase enzyme in a RNA synthesis-dependent manner. Elevated intracellular calcium levels contribute to the stimulation apparently by increasing the availability of endogenous arachidonate for subsequent conversion to PGE2.
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PMID:Stimulation of human amnion prostaglandin E2 production by activators of protein kinase-C. 246 Apr 86

Active tumor promoters such as 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or membrane-diffusible synthetic diacylglycerols such as 1,2-dioctanoyl-sn-glycerol (DiC8), which specifically activate protein kinase C (PKC), inhibited the agonist-mediated rise in cytosolic calcium [(Ca2+)i] in a mast cell line (PB-3c) and human platelets. TPA inhibition of agonist-mediated calcium transient in platelets was readily reversed by the PKC inhibitor staurosporine. In contrast to DiCs, only active tumor promoters induced a time- and dose-dependent translocation of cytosolic PKC to membranes as determined both enzymatically or by immunoblotting. However, the concentration of TPA required to induce a half-maximal subcellular redistribution of immunodetectable PKC activity was an order of magnitude greater than the half-maximal dose required to inhibit the intracellular rise in (Ca2+)i. Thus, activation of PKC seems not to be exclusively coupled to its translocation to membranes, suggesting that translocation of PKC is mainly involved in the down-regulation of PKC. Down-regulation of immunoprecipitable PKC was studied in various human breast cancer cell lines that display differential growth inhibitory responses toward the tumor promoter. TPA induced translocation of [35S]methionine-prelabeled cytosolic 80 kDa PKC to membranes followed by complete degradation of the enzyme (t1/2 = 2 h) without affecting PKC synthesis. During prolonged TPA exposure, 20-80% of total 80 kDa PKC of control cells was still synthetized as a membrane-bound 74/80 kDa PKC doublet. Although both proteins lacked PKC activity and phorbol ester binding, they revealed structural similarity with the active 80 kDa PKC form of untreated cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of protein kinase C (PKC) in short- and long-term cellular responses: inhibition of agonist-mediated calcium transients and down-regulation of PKC. 246 82


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