Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calmodulin antagonists inhibited hormone-stimulated cyclic AMP accumulation in both cultured cells and cell lysates of mouse B16 melanoma. Particulate preparations of B16 melanoma contained 34-45% of total cell calmodulin, which could not be dissociated by extensive washing irrespective of the presence of EGTA in the buffer. The adenylate cyclase activity in such preparations was unaffected by the addition of exogenous calmodulin. However, the rare-earth-metal ion La3+, which can mimic or replace Ca2+ in many systems, produced an immediate inhibition of agonist-stimulated adenylate cyclase activity and preincubation of particulate preparations was La3+ followed by washing with La3+-free buffer dissociated calmodulin (96% loss) from particulate preparations. The loss of calmodulin from particulate preparations was associated with a decrease in agonist responsiveness (74%) and a marked change in the Ca2+-sensitivity of the enzyme, low concentrations of calcium (approx. 10 nM) now failing to stimulate enzyme activity, high concentrations of calcium (greater than or equal to 100 nM) producing greater-than-normal inhibition of enzyme activity. Direct activation of adenylate cyclase by the addition of pure calmodulin was now demonstrable in such calmodulin-depleted particulate preparations. Half-maximal stimulation of agonist-responsive adenylate cyclase occurred at 80 nM-calmodulin in the presence of 10 microM free Ca2+. Maximal stimulation by calmodulin (at 300-600 nM) restored enzyme activity to 89 +/- 5% (mean +/- S.E.M., n = 7) of the activity in untreated, calmodulin-intact, preparations.
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PMID:Calmodulin activation of adenylate cyclase in the mouse B16 melanoma. 609 17

5-Bromodeoxyuridine (BUdR) causes mouse melanoma cells to develop a flattened morphology and simultaneously adhere tenaceously to the substratum on which they are growing. Experiments were done to determine if these events are coupled to increases in cAMP levels and to rearrangements in the cells' cytoskeleton. Cyclic AMP assays revealed that cell flattening and the increase in adhesive properties caused by BUdR is not accompanied by an increase in the cellular concentration of cyclic AMP. However, electron micrographs of cells grown in the presence of BUdR show a striking increase in the number of organized microtubules and microfilaments. Colchicine binding revealed no difference in the amount of tubulin present in untreated or BUdR-treated cells indicating that the increase in the number of microtubules is due to the polymerization of pre-existing tubulin subunits. These results are discussed in light of possible similar mechanisms of action of BUdR and cyclic AMP in regulating the organization of microtubules and microfilaments and the role these structures play in altering cell morphology and adhesive properties.
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PMID:The effects of 5-bromodeoxyuridine on cyclic AMP levels and cytoskeletal organization in malignant melanoma cells. 624 51

The influence of all trans-retinoic acid on cyclic AMP metabolism was examined in B16-F1 mouse melanoma cells. Treatment of these cells with retinoic acid resulted in a dose-dependent inhibition of cell growth which was accompanied by a concentration-dependent increase in both basal and cyclic AMP-stimulated protein kinase activity, Intracellular levels of cyclic AMP, however, were not altered by retinoid treatment. A protein kinase-deficient variant of B16-F1 (MR-4) did not exhibit decreased growth or increased protein kinase activity in response to retinoic acid treatment. At least 24 h of incubation was required before increased protein kinase activity could be detected in treated B16-F1 cells. Retinoic acid treatment increased the Vmax of protein kinase, but the Ka for cyclic AMP activation was not altered. These findings suggest that in B16 mouse melanoma cells, cyclic AMP-dependent protein kinase may be a target for the growth inhibitory effects of the retinoid.
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PMID:Retinoic acid increases cyclic AMP-dependent protein kinase activity in murine melanoma cells. 624 11

Cloudman S91 mouse melanoma cells lose their ability to demonstrate an MSH-induced increase in tyrosinase activity as cell density increases. This loss in hormone responsiveness occurs before confluency is reached and cannot be reversed by exposure of cells to increasing concentrations of MSH. The failure of high-density cultures to respond to MSH is apparently not the result of an inability of MSH to stimulate cAMP production, since either low- or high-density cultures exposed to MSH demonstrate equivalent increases in intracellular levels of cAMP. Further, neither theophylline (1mM), dibutyryl cyclic AMP (10(-4)M), or prostaglandin E1 (10(-6)M) is effective in stimulating tyrosinase activity in melanoma cells cultured at densities exceeding 6 X 10(4) cells/cm2. This finding suggests that the decay of hormone responsiveness occurs at a cellular site distal to cAMP production. The decrease in tyrosinase stimulation by MSH as cell density increases is also apparently not the result of an increase in activity of any soluble inhibitor of the enzyme, for cytosol preparations from high-density cultures (10(5) cells/cm2) fail to inhibit tyrosinase activity in cell homogenates from low-density cultures treated with MSH.
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PMID:Decay of hormone responsiveness in mouse melanoma cells in culture as a function of cell density. 625 96

Studies were performed for the investigation of endocrine responsiveness in cell lines derived from either normal human melanocytes or human melanoma cells. Alterations in differentiation (tyrosinase activity) were determined in cells exposed to either melanocyte-stimulating hormone (MSH, 10(-7) M), theophylline (10(-3) M), N6,O2'-dibutyryl cyclic AMP (db-cAMP, 10(-4) M), or prostaglandin E1 (PGE1, 10(-6) M). Cultures derived from normal uveal melanocytes demonstrated increased tyrosinase activity upon exposure to either theophylline, db-cAMP, or PGE1, but not to MSH. However, MSH responsiveness was detected in 7 of 11 human melanoma cell lines. Four cell lines demonstrated increased activity of tyrosinase after MSH treatment, whereas three lines showed an MSH-induced inhibition of enzyme activity. PGE1 was effective in stimulating tyrosinase activity in five of nine cell lines examined. Theophylline was the most effective stimulator of tyrosinase in melanoma-derived cell populations and caused increased enzyme activity in eight of eleven cell lines.
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PMID:Endocrine responsiveness in human melanocytes and melanoma cells in culture. 626 56

Because tumor-induced platelet aggregation appears to play a role in the development of certain experimental tumor metastases, we examined the mechanism(s) of tumor-induced platelet aggregation as well as the effect of various anti-platelets agents. Two mechanisms for tumor-induced platelets aggregation have been previously described: (1) a mechanism which requires complement, a stable plasma factor, divalent cation and a sialo-lipo-protein vesicular component of the tumor membrane for platelet aggregation; and (2) a mechanism which operates via the generation of thrombin and requires a phospholipid component of the tumor membrane. We now report a new mechanism of tumor-induced platelet aggregation which is shared by three different tumors: a spontaneously metastatic human melanoma, HM29, a murine melanoma, B16F10, and a carcinogen-induced metastatic murine colon carcinoma, CT26. These tumors do not require cell-surface sialic acid or serum complement as does the first mechanism. They do not require cell-surface phospholipid, as do the tumors representing the other two mechanism. They do not aggregate platelets via the generation of thrombin as do tumors representing the second mechanism. These tumors are unique in that they require a trypsin-sensitive surface protein for activity. The ability of the thrombin-generating tumors to aggregate platelets is uniquely sensitive to two highly specific, synthetic thrombin-competitive inhibitors: DAPA and No. 805. The other two groups of tumors are at least 10 times more sensitive to inhibition of platelet aggregation by elevation of cyclic AMP levels (prostacyclin, 6-keto-PGE1, dibutyryl cyclic AMP) and at least 10 times more sensitive to inhibition of prostaglandin synthesis (indomethacin, ibuprofen). Thus, tumor-induced platelet aggregation is heterogeneous with respect to mechanism of action as well as inhibition by anti-platelet pharmacologic agents. Sensitivity to anti-platelet agents correlates with the mechanism by which tumor cells aggregate platelets.
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PMID:A new mechanism for tumor induced platelet aggregation. Comparison with mechanisms shared by other tumor with possible pharmacologic strategy toward prevention of metastases. 629 77

Metastasis is a complex process whereby tumour cells from a primary neoplastic growth disseminate throughout the body and establish secondary tumour foci in distant organs. Biochemical traits associated with, or essential for, the expression of the metastatic phenotype have not yet been identified. In the course of examining stimulation of the B16 murine melanoma adenylate cyclase by melanocyte-stimulating hormone (MSH) and by the diterpene forskolin, we noted that tumour cell clones isolated from common parent cell populations differed widely in their responses to these agonists. We report here that the accumulation of cyclic AMP induced by MSH or forskolin shows a strong positive correlation with the ability of B16 melanoma clones to form pulmonary tumour colonies when injected intravenously (i.v.) into syngeneic mice ('experimental metastasis'). In parallel in vitro analyses of cyclic AMP metabolism and in vivo assays of experimental metastasis using replicate cell preparations, highly metastatic tumour cell clones consistently show greater than a 30-fold increase in cellular cyclic AMP when exposed to MSH or forskolin. By contrast, clones with limited metastatic abilities respond to the same agonists with only a two- to threefold increase in cellular cyclic AMP. These data suggest that cyclic AMP metabolism is linked with biochemical pathways that are responsible for the formation of experimental metastasis by the B16 melanoma.
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PMID:Experimental metastasis correlates with cyclic AMP accumulation in B16 melanoma clones. 632 99

Two partially purified fractions of the ethanol precipitate (70-95%) of the water extract of Harding-Passey mouse melanoma, which inhibit protein and DNA syntheses of B-16 melanoma cells in culture, also inhibit protein synthesis in various cell-free systems. By examining their inhibitory effects on limited reactions of protein synthesis, it was found that one of them (ME II) inhibits protein synthesis by blocking aminoacyl-tRNA formation, while the other (ME IV) does not. This inhibition of aminoacyl-tRNA formation was not limited to specific amino acids. Since the amino acid-dependent pyrophosphate (PPi)-ATP exchange reaction catalyzed by aminoacyl-tRNA synthetases was not inhibited, it was concluded that some factor(s) in ME II inhibits amino acid transfer from aminoacyl-AMP to tRNA. ME II contains more than 20 proteins from 10,000 to 90,000 daltons. EDTA treatment of this fraction caused the release of low-molecular substances with inhibitory activity from the proteins. The molecular weights of the active substances are less than 5,000 daltons. The active low-molecular substances are apparently not peptides or nucleotides.
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PMID:Inhibition of aminoacyl-transfer RNA formation by low-molecular substances from melanoma extract. 632 50

Leukocytes from patients with early cancer exhibit leukocyte adherence inhibition (LAI) when incubated with extracts of cancer of the same organ and histogenesis, whereas leukocytes from patients with advanced cancer seldom do. To understand the reason for this refractory state, tumor antigen-induced LAI and transmembrane signalling were measured in the same leukocytes. Transmembrane signalling was measured by changes in membrane potential (delta psi) by the [3H]tetraphenylphosphonium equilibration technique. When leukocytes from patients with early breast cancer were incubated with extracts of breast cancer and malignant melanoma they showed delta psi changes consisting of depolarization and hyperpolarization beginning within 0.5 min after addition of the breast cancer extract and finishing 15 min later. Moreover, they showed no delta psi changes when incubated with extracts of normal breast tissue. Leukocytes from subjects without cancer seldom showed delta psi changes. In criss-cross experiments, leukocytes from patients with melanoma only exhibited delta psi changes when incubated with the melanoma extract. There was a strong correlation between cancer extract-induced delta psi change and LAI. The delta psi change was triggered by leukotriene-like mediators from antibody-dependent monocytes. Authentic leukotrienes triggered delta psi changes in all subpopulation of leukocytes. Leukocytes from patients with advanced breast cancer when incubated with breast cancer extract did not transmit a signal or show LAI. Brief elevation of intracellular cyclic AMP restored both delta psi change and LAI induced by breast cancer extracts, indicating that reactive leukocytes are present but in a refractory state. We conclude that leukocytes from patients with advanced cancer do not react in LAI because tumor antigen does not trigger a transmembrane signal to initiate the cascade of biochemical reactions and physiological changes for LAI.
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PMID:Transmembrane signal defect and absence of cancer extract induced leukocyte adherence inhibition (LAI) for leukocytes from patients with advanced cancer. 633 70

The synthetic glucocorticoid, triamcinolone acetonide, was found to increase melanogenesis in the human melanoma cell line NEL. Treatment of NEL cells for 24 hr with triamcinolone acetonide (1 X 10(-7) M) increased the activity of the enzyme tyrosinase by 43% and the incorporation of the melanin precursor, L-3,4-dihydroxyphenylalanine, by 23%. Additional studies revealed no change in cyclic AMP levels over an 18-hr test period. A 2-hr preincubation of NEL cells with actinomycin D (10 micrograms/ml) prevented the increase in tyrosinase activity by triamcinolone acetonide. When triamcinolone acetonide was added to a synchronized population of NEL cells, an increase in tyrosinase activity was observed at 16 hr, coinciding with the late S phase of the cell cycle. These results suggest that glucocorticoids are involved in the regulation of melanogenesis in NEL cells by increasing the activity of the rate-controlling enzyme tyrosinase.
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PMID:Effect of triamcinolone acetonide on tyrosinase activity in a human melanoma cell line. 642 29


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