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)

Accumulation of Ca2+ (+ phosphate) by respiring mitochondria from Ehrlich ascites or AS30-D hepatoma tumor cells inhibits subsequent phosphorylating respiration in response to ADP. The respiratory chain is still functional since a proton-conducting uncoupler produces a normal stimulation of electron transport. The inhibition of phosphorylating respiration is caused by intramitochondrial Ca2+ (+ phosphate). ATP + Mg2+ together, but not singly, prevents the inhibitory action of Ca2+. Neither AMP, GTP, GDP, nor any other nucleoside 5'-triphosphate or 5'-diphosphate could replace ATP in this effect. Phosphorylating respiration on NAD(NADP)-linked substrates was much more susceptible to the inhibitory effect of intramitochondrial Ca2+ than succinate-linked respiration. Significant inhibition of oxidative phosphorylation is given by the endogenous Ca2+ present in freshly isolated tumor mitochondria. The phosphorylating respiration of permeabilized Ehrlich ascites tumor cells is also inhibited by Ca2+ accumulated by the mitochondria in situ. Possible causes of the Ca2+-induced inhibition of oxidative phosphorylation are considered.
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PMID:Inhibition of oxidative phosphorylation in ascites tumor mitochondria and cells by intramitochondrial Ca2+. 676 37

Initial velocity measurements of [3H]ADP and [3H]ATP uptake have been made with mitochondria isolated from Morris hepatomas of differing growth rates, and factors known to influence the rates of nucleotide exchange have been examined in an effort to determine whether the elevated rates of aerobic glycolysis in these tumors can be attributed to altered carrier activity. These studies included the determination of the apparent kinetic constants for nucleotide uptake as a function of the mitochondrial energy state and the dependence of transport rates on temperature. Also included in these studies were measurements of the mitochondrial levels of endogenous inhibitors, divalent cations and internal adenine nucleotides. Results obtained showed that with mitochondria isolated from the various tumor lines, the apparent kinetic constants for nucleotide uptake are different from those of control rat or regenerating liver mitochondria; the apparent Vmax values for both ADP and ADP uptake are significantly lower. Furthermore, under conditions of a high-energy state, the Km and Vmax values for ATP uptake are greater than the Km and Vmax value for ADP uptake but that under uncoupled conditions, the opposite is observed. Comparison of the levels of mitochondrial Ca2+, Mg2+, long-chain acyl-CoA ester and adenine nucleotide from the various mitochondria showed that important differences exist between liver and hepatoma mitochondria in the levels of Ca2+, long-chain acyl-CoA ester and AMP. Mitochondrial Ca2+ levels are elevated 3-5--fold in all tumor lines, and for Morris 7777 hepatoma (a rapidly growing tumor) by a remarkable 70-fold; whereas the levels of acyl-CoA ester and AMP are significantly lower in the more rapidly growing tumors. Arrhenius plots for nucleotide uptake in mitochondria from liver and hepatoma are characterized as being biphasic, having similar activation energies above and below the break point temperature (28-38 and 6-16 kcal/mol, respectively). However, the transition temperature for mitochondria from the various hepatomas is uniformly 4-5 degrees C lower than mitochondria from control liver. The latter difference may reflect a variation in membrane composition, most probably lipid components. It is concluded that the presence of elevated levels of Ca2+ and lower levels of AMP in hepatoma mitochondria and difference of membrane compositions may play an important role in limiting adenine nucleotide transport activity in vivo and that the impaired carrier activity may contribute to higher rates of aerobic glycolysis observed in these tumors.
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PMID:Adenine nucleotide transport in hepatoma mitochondria. Characterization of factors influencing the kinetics of ADP and ATP uptake. 683 Jul 67

A cyclic-nucleotide independent heparin-sensitive nuclear protein kinase (NII) from the Morris hepatoma 3924A has been purified by a combination of ion exchange and affinity chromatographic procedures and velocity gradient centrifugation. The purified kinase had a molecular weight of 140,000 as determined by gel filtration. Two polypeptides (Mr = 42,000 and 25,600) were present in the purified preparation in approximately equimolar concentrations. The protein kinase employed Mg2+ and Co2+ as divalent ion and preferred the nonhistone proteins, casein or phosvitin, as protein acceptors. In the presence of Mg2+, it utilized both ATP and GTP as substrates and transferred the terminal nucleotide phosphate to serine and threonine residues of the protein acceptor. Phosphorylation of casein was stimulated by polyamines, particularly spermine. This polyamine preferentially enhanced phosphate transfer to threonine. The enzyme was inhibited by several compounds including heparin, the o-n-octyloxime of rifamycin (AF/013), 3'-dATP, o-phenanthroline, polynucleotides, and ADP. Of these inhibitors, heparin was the most potent and completely abolished kinase activity at a concentration of 0.1 micrograms/ml. The kinase could be autophosphorylated by incubation with Mg2+ and [gamma-32P]ATP; under these conditions phosphorylation was confined to the polypeptide of Mr = 24,600 and was completely inhibited by heparin. Based on the unique properties of NII protein kinase (ability to use GTP, stimulation by spermine, sensitivity to heparin), a selective assay was developed which could measure NII activity in the presence of other nuclear kinases. Under the optimal assay conditions, the nuclear extract of hepatoma 3924A was found to contain at least five times more NII kinase activity than that of normal adult liver. Analysis of extensively purified preparations from the two sources confirmed these results. After purification 11 times more NII protein kinase activity was obtained from hepatoma 3924A than from liver. Although hepatoma and liver protein kinases exhibited many common properties, they displayed distinct nucleotide saturation kinetics. The apparent Km for ATP was 10 microM for hepatoma protein kinase and 24 microM for the liver enzyme.
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PMID:A heparin-sensitive nuclear protein kinase. Purification, properties, and increased activity in rat hepatoma relative to liver. 725 4

Lipoperoxidation by rat liver homogenates increases after in vivo administration of CCl4, colchicine and CHM. In vitro a strong lipoperoxidative action was found for ADP/Fe3+, ethionine and glucosamine. No lipoperoxidation was elicited by hepatomatous liver or by hepatoma cells.
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PMID:Effects of various metabolic inhibitors on lipoperoxidation by homogenates of normal, regenerating and hepatomatous rat liver and by hepatoma cells. 733 Apr 58

For many years after Warburg's classic work, it was generally assumed that tumors produced large amounts of lactic acid and consequently had an acidic intracellular pHi. However, with the advent of Magnetic Resonance Spectroscopy (MRS), a non-invasive in vivo measure of tissue pH became available and demonstrated that in both human and animal tumors, pHi was higher (> 7.0) than pH epsilon (< 6.8), in contrast to normal tissues (e.g., liver) in which pHi (approximately 7.2) is lower than pH epsilon (approximately 7.4). This result has been confirmed in animal tumors using an MRS-visible extracellular marker, 3-aminopropyl phosphonate. The pH gradient across the tumor cell membrane is part of an interrelated system of ionic gradients and measurements made by both 31P MRS and by conventional analysis in Morris hepatoma 9618a and in livers demonstrated that the following ions also changed: compared with liver the Na+ content was 2-fold higher, K+ was 20% lower, total Ca2+ was 8-fold higher (7.4 mumol/g wet wt) and total Pi 2-fold higher (8.5 mumol/g wet wt), suggesting the presence of insoluble calcium phosphate, HCO3- was lower, total Mg2+ was similar in both tissues, but free [Mg2+] (calculated by two different methods) was approximately 5-fold lower in the hepatoma, as was [ATP]/[ADP][P(i)]. Because of an inadequate blood supply, tumors are often hypoxic with impaired Krebs cycle activity, low [ATP]/[ADP][P(i)] and rely mainly on glycolysis for energy. The rapid production and subsequent export of anionic lactate-from the tumor cell would be accompanied by H+. This would account for reversal of the proton gradient and activation of the Na+/H+ exchange. The elevated [Na+]i would decrease the Na+/Ca2+ exchange, which would in turn tend to cause the accumulation of Ca2+ (and P(i)). Such calcification is a very common feature of tumor pathology. The data indicate the change in gradient of one ion (H+) involves alterations in the linked equilibria of many ions and also of energy metabolites and offers new insights into properties of tumors important both diagnostically and therapeutically.
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PMID:Tumor metabolism: the lessons of magnetic resonance spectroscopy. 757 38

The transmembrane transduction mechanism coupled to purinergic receptors has been studied in a rat hepatoma cell line (N1S1) at the single cell level by a combination of microfluorimetric and electrophysiological techniques. ATP in the micromolar range causes release of Ca2+ from internal stores and consequent opening of Ca(2+)-activated K+ channels, leading to membrane hyperpolarization. The order of potency of the various nucleotides tested is UTP = ATP = ADP >> AMP, and ATP > beta, gamma-CH2 ATP, indicating that these receptors belong to the P2U subtype. The Ca2+ rise induced by various amounts of ATP exhibits an all-or-none behaviour already observable at 10 microM ATP. Intracellular injection of (10-20 microM) InsP3 or of its non-metabolizable analogue 3-F-InsP3 through the patch pipette, does not always result in a Ca2+ rise. These results may be interpreted assuming that the InsP3 receptors-Ca2+ release channels involved in the purinergic/pyrimidinergic stimulation are located in a subcellular compartment not easily accessible from the bulk cytosol and that a positive feedback loop occurs in this restricted space.
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PMID:Characteristics of the signal transduction system activated by ATP receptors in the hepatoma cell line N1S1-67. 785 82

Starvation of mouse hepatoma cells for essential amino acids or glucose results in the ADP-ribosylation of the molecular chaperone BiP/GRP78. Addition of the missing nutrient to the medium reverses the reaction. The signal mediating the response to environmental nutrients involves the translational efficiency. An inhibitor of proteins synthesis, cycloheximide, or reduced temperature, both of which reduce translational efficiency, stimulate the ADP-ribosylation of BiP/GRP78. Inhibition of N-linked glycosylation of proteins results in the overproduction of BiP/GRP78. The over produced protein is not ADP-ribosylated suggesting that this is the functional form of BiP/GRP78. The over produced BiP/GRP78 can, however, be ADP-ribosylated if the cells are starved for an essential amino acid. BiP/GRP78 resides in the lumen of the endoplasmic reticulum where it participates in the assembly of secretory and integral membrane proteins. ADP-ribosylation of BiP/GRP78 during starvation is probably part of a nutritional stress response which conserves limited nutrients by slowing flow through the secretory pathway.
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PMID:ADP-ribosylation of the molecular chaperone GRP78/BiP. 789 57

In heparinized human platelet-rich plasma (PRP), J-7 human hepatoma cells initially induced platelet aggregation; then a clot formed. ADP-scavenger systems, apyrase and creatine phosphate/creatine phosphokinase did not inhibit this tumor-cell-induced platelet aggregation (TCIPA), whereas hirudin and concanavalin A completely blocked it. J-7 cells also shortened the recalcification time of normal and of Factor-VIII- and IX-deficient human plasma, although it was inactive in shortening the recalcification time of Factor-VII-deficient plasma. After treatment with phorbol 12,13-dibutyrate (PDBu) for 5 to 90 min, the aggregation and coagulation abilities of J-7 cells were unaffected. Prolonged treatment of J-7 cells with PDBu but not with alpha-PDBu for 24 and 72 hr resulted in gradual loss of aggregation and coagulation. Staurosporine antagonized the effect of PDBu and restored aggregation and coagulation in J-7 cells. Protracted treatment with PDBu (24 or 72 hr) did not affect adherence of J-7 cells to the extracellular-matrix proteins (i.e., fibrinogen, fibronectin, laminin, vitronectin and collagen types I and IV) or to the surface of plastic culture dishes. The treatment also did not affect J-7 cell detachment from plastic culture dishes. These in vitro results demonstrate that protracted phorbol ester treatment diminishes TCIPA and blood coagulation of tumor cells.
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PMID:Protracted treatment with phorbol ester modulates J-7 human hepatoma-cell-induced aggregation and coagulation of human platelet-rich plasma. 796 Feb 44

1. The distribution of control of the rate of state 3 respiration of AS-30D hepatoma mitochondria was determined. 2. The ATP/ADP carrier (flux control coefficient, Ci = 0.70) and the ATP synthase (Ci = 0.19-0.32) were the only steps that exerted significant control on the phosphorylating flux supported by either glutamate+malate, pyruvate+malate, or succinate+rotenone. This is in contrast to liver mitochondria where the control is distributed between several steps. 3. It is suggested that this pattern of control of phosphorylation in hepatoma mitochondria is a consequence of a lower content of adenine nucleotides or a higher content of Mg2+.
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PMID:Control of oxidative phosphorylation in AS-30D hepatoma mitochondria. 809 69

Fractions A (salted out by ammonium sulphate between 21-30% saturation), and fractions B (salted out between 51-70% saturation) of pyruvate kinase (EC 2.7.1.40.) corresponding respectively to pyruvate kinase types L and M2 from rat liver and Morris hepatoma 7777 were purified by an affinity chromatography on Blue Sepharose CL-6B. Peaks of inactive proteins were eliminated and the enzyme fractions bound biospecifically to the gels were eluted by free ADP. The molecular mass of purified hepatoma pyruvate kinase fraction B was smaller than that of liver pyruvate kinase fraction B. Morris hepatoma pyruvate kinase fraction B represented a variant of type M2, characterised by greatest affinity to 2-phosphoenolpyruvate as a main substrate and different sensitivity to low-molecular effectors in comparison with types L from both liver and hepatoma and in comparison with type M2 from normal rat liver. Only this hepatoma fraction B showed a tumour specific sensitivity to L-cysteine and was insensitive to normal signal molecules i.e. to ATP and fructose-1,6-diphosphate which influence liver pyruvate kinase activity. L-Cysteine inhibited the tumour fraction B of pyruvate kinase by decreasing its Vmax and increasing the Km values in relation to 2-phosphoenolpyruvate.
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PMID:Comparison of pyruvate kinase variants from rat liver and Morris hepatoma 7777, obtained by an affinity chromatography on blue sepharose CL-6B. 821 64


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