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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the mechanisms of homologous and heterologous regulation of PTH receptor binding and receptor-mediated adenylate cyclase activity in the osteosarcoma cell line UMR-106. Pretreatment with PTH resulted in a time- and dose-dependent decrease in PTH-stimulated adenylate cyclase which was maximal after 2 h and at a concentration of 10(-8) M rat (r)PTH-(1-34). PTH pretreatment over the same dose range also diminished receptor binding of 125I-labeled rPTH-(1-34); however, maximal loss of binding required 14 h and was greater than the loss of maximal adenylate cyclase activity. After 24 h pretreatment with rPTH-(1-34), cell surface receptors were decreased from 21,000 sites per cell to 2,700 sites per cell, and these down-regulated PTH receptors could not be detected in either vesicular or cytosolic subcellular fractions. Recovery from such homologous down-regulation appeared to require new receptor synthesis. Heterologous down-regulation of PTH receptors was demonstrated when UMR-106 cells were preincubated with prostaglandin E2 or (Bu)2cAMP. Heterologous desensitization was shown to be the result of a reversible modification of the PTH receptor which decreased binding affinity and decreased PTH-stimulated adenylate cyclase. Postreceptor components were also examined, and PTH but not prostaglandin E2 pretreatment was shown to decrease guanyl nucleotide binding (G) protein-mediated adenylate cyclase stimulation. This decrease in G protein function was associated with a loss of cholera toxin-catalyzed ADP ribosylation and was also detected by immunoblotting. These results indicate that PTH responses in osteoblastic cells are modulated by diverse mechanisms involving modifications both to the receptor and to postreceptor components of adenylate cyclase.
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PMID:Mechanisms of homologous and heterologous regulation of parathyroid hormone receptors in the rat osteosarcoma cell line UMR-106. 215 32

The influence of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on adenylate cyclase responsiveness in cultured osteoblastic cells was studied using a human osteosarcoma cell line SaOS-2. 1,25(OH)2D3 treatment had no effect on cell growth, cell protein and alkaline phosphatase activity. 1,25(OH)2D3 did not alter the basal production of cyclic AMP (cAMP) in intact cells, but the cAMP formation in response to parathyroid hormone (PTH), isoproterenol (ISO) and cholera toxin was attenuated by 1,25(OH)2D3. The response to forskolin, however, was unaffected by 1,25(OH)2D3 treatment. Islet activating protein failed to modify these 1,25(OH)2D3 effect. In cell free experiments, 1,25(OH)2D3 showed similar effect--that is, PTH and ISO-stimulated adenylate cyclase activity were attenuated, but forskolin-stimulated adenylate cyclase was unaffected. 1,25(OH)2D3 treatment had no effect on the kinetics of PTH binding to PTH receptor and on the ADP ribosylation of GTP stimulatory binding protein (Gs) in SaOS-2 cells. According to these results, 1,25(OH)2D3 appeared to change the coupling of Gs with adenylate cyclase, but does not affect receptor, Gs and adenylate cyclase themselves, nor GTP inhibitory binding protein.
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PMID:The effect of 1,25-dihydroxyvitamin D3 on human osteoblast-like osteosarcoma cell: modification of response to PTH. 216 Dec 22

Two new compounds, 4-[4-[bis-(2-chloroethyl)-amino-]phenyl]-1- hydroxybutane-1,1-bisphosphonic acid (BAD) and aminotris-(methylenephosphonato)-diamminoplatinum(II) (ADP) that both have cytostatic and osteotropic properties, have shown good therapeutic efficacy against an osteosarcoma which metastasizes and kills by lung metastases. We therefore combined each of these drugs with the antimetastic agent razoxane. Razoxane (20 mg/kg i.p., 5 days/week for 6 weeks) was administered in combination with either BAD (30 mg/kg i.p.) or ADP (37.5 mg/kg i.v.) twice weekly for 3 weeks. Tumour volumes, body weight, survival time and occurrence of metastases were recorded, in addition to the measurement of the metastasis area compared to the total lung area in serial histological lung samples. In both experiments, razoxane effected a significant increase in life span while being ineffective in tumour inhibition. Razoxane in combination with BAD displayed an enhanced anticancer activity which was not significant. ADP had a good antineoplastic activity and a large increase in survival time (144 per cent ILS). Razoxane used in combination with ADP did not influence antitumour efficacy. Median survivals of both ADP-treated groups were significantly longer than the razoxane-treated group. Analysis of the lung metastasis area showed a maximum of 57 per cent for the controls while all treated groups occupied a lesser area. The lowest metastases area was found with the combination treatment BAD + RAZ (18 per cent). This was considered an antimetastatic effect, while ADP treatment effected a time delay only. No change in metastatic pattern was observed in any of the treatment groups. Histological examination showed no effect on the capillaries in the proliferating region of the tumours that could account for the lower occurrence of metastases.
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PMID:Therapeutic efficacy of two different cytostatic-linked phosphonates in combination with razoxane in the transplantable osteosarcoma of the rat. 235 Sep 20

The effects of transforming growth factor beta (TGF beta) on parathyroid hormone (PTH)-responsive adenylate cyclase were examined in clonal rat osteosarcoma cells (UMR-106) with the osteoblast phenotype. Purified TGF beta incubated with UMR-106 cells for 48 hr produced a concentration-dependent increase in PTH stimulation of adenylate cyclase, with maximal increase in PTH response (37%) occurring at 1 ng/ml TGF beta. TGF beta also enhanced receptor-mediated activation of adenylate cyclase by isoproterenol and prostaglandin E2 (PGE2) and nonreceptor-mediated enzyme activation by cholera toxin and forskolin. In cells in which PTH-stimulated adenylate cyclase activity was augmented by treatment with pertussis toxin, the incremental increase in PTH response produced by TGF beta was reduced by 33%. However, TGF beta neither mimicked nor altered the ability of pertussis toxin to catalyze the ADP-ribosylation of a 41,000-Da protein, presumably the alpha subunit of the inhibitory guanine nucleotide-binding regulatory component (Gi) of adenylate cyclase, in cholate-extracted UMR-106 cell membranes. TGF beta also had no effect on the levels of alpha or beta subunits of Gi, as assessed by immunotransfer blotting. In time course studies, brief (less than or equal to 30 min) exposure of cells to TGF beta during early culture was sufficient to increase PTH response but only after exposed cells were subsequently allowed to grow for prolonged periods. TGF beta enhancement of PTH and isoproterenol responses was blocked by prior treatment of cells with cycloheximide but not indomethacin. The results suggest that TGF beta enhances PTH response in osteoblast-like cells by action(s) exerted at nonreceptor components of adenylate cyclase. The effect of TGF beta may involve Gi, although in a manner unrelated to either pertussis toxin-catalyzed ADP-ribosylation of the alpha subunit of Gi or changes in levels of Gi subunits. The regulatory action of TGF beta on adenylate cyclase is likely to be mediated by the rapid generation of cellular signals excluding prostaglandins, followed by a prolonged sequence of events involving protein synthesis. These observations suggest a mechanism by which TGF beta may regulate osteoblast responses to systemic hormones.
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PMID:Transforming growth factor beta enhances parathyroid hormone stimulation of adenylate cyclase in clonal osteoblast-like cells. 239 78

We examined mechanisms of down-regulation of PTH receptors and desensitization of the PTH-stimulated increase in intracellular cAMP in clonal rat osteosarcoma cells, ROS 17/2.8. ROS cells treated with 10 nM [Nle8,Nle18,Tyr34] bovine (b) PTH-(1-34) amide (NlePTH) for 3 days showed loss of specific PTH binding and PTH-stimulated cAMP accumulation to 10% of that in vehicle-treated control cells. Treatment of these cells with both 0.5 mM 8-bromo-cAMP (8-Br-cAMP) and 1 mM methylisobutylxanthine or 100 ng/ml cholera toxin for 3 days elicited no change in either of these responses. Treatment with 10 nM NlePTH for 3 days did not modify the cAMP accumulation stimulated by 30 microM forskolin or 1 micrograms/ml cholera toxin, indicating that agonist-specific desensitization of PTH-stimulated cAMP accumulation is not due to diminished activity of either the stimulatory guanyl nucleotide regulatory subunit (Gs) or the catalytic subunit of the adenylate cyclase. Treatment of ROS cells with pertussis toxin (PT; 10 ng/ml) for 12, 24, 48, and 72 h increased specific PTH binding by 21%, 28%, 35%, and 39%. The increase in PTH binding was associated with a parallel increase in PTH-stimulated cAMP accumulation and was due to an increase in the number of PTH receptors. PTH receptor affinity remained constant (apparent Kd = 0.3 nM). PT treatment of the cells partially blocked agonist-specific PTH receptor down-regulation. PT catalyzed ADP ribosylation of 41K and 39K membrane proteins, consistent with the alpha-subunits of Gi and Go, respectively. In conclusion, agonist-induced PTH receptor down-regulation in ROS 17/2.8 cells is cAMP independent and can be reversed by PT treatment. PTH receptor expression in these cells appears to be under tonic inhibitory control by mechanisms involving a PT-sensitive G protein(s).
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PMID:Inactivation of pertussis toxin-sensitive guanyl nucleotide-binding proteins increase parathyroid hormone receptors and reverse agonist-induced receptor down-regulation in ROS 17/2.8 cells. 247 33

In rat osteosarcoma (ROS 17/2.8) cells, which express osteoblastic features in culture, basic fibroblast growth factor (bFGF) reduces the level of alkaline phosphatase, type I collagen, and osteocalcin mRNA and increases osteopontin mRNA, independent of growth stimulation. The fibroblast growth factor (FGF) effects are dose dependent (EC50 about 6 pM) and are detected 24 h after addition of the growth factor. bFGF also reduces parathyroid hormone-stimulatable adenylate cyclase and alkaline phosphatase activity in these cells. Concomitant treatment with pertussis toxin (20 ng/ml) opposes the FGF effects. Although cyclic AMP elevating agents mimic pertussis toxin action on some parameters, they produce opposite effects on others, indicating that antagonism between pertussis toxin and bFGF is not mediated by cyclic AMP. bFGF caused a small reduction in steady state NAD-dependent ADP-ribosylation and had no detectable effects on the steady-state levels of the Gi alpha (alpha subunit of the inhibitory G protein) 1, 2, and 3, visualized with specific antibodies in these cells. Although the site of interaction of pertussis toxin and FGF remains to be determined, the findings presented here suggest separate control of growth and differentiation by bFGF and show that pertussis toxin treatment can modulate differentiation in these cells, presumably via Gi proteins.
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PMID:Opposing effects of fibroblast growth factor and pertussis toxin on alkaline phosphatase, osteopontin, osteocalcin, and type I collagen mRNA levels in ROS 17/2.8 cells. 247 40

Retinoic acid (RA) inhibits the increases in alkaline phosphatase (AP) and hormone-stimulated adenylate cyclase that accompany the growth of ROS 17/2.8 osteosarcoma cells in culture. The RA effects were first detected 2 days after initiation of treatment and were dose dependent, with an EC50 of 100 nM. The reduction in the hormone-responsive adenylate cyclase activity was associated with lower levels of beta-catecholamine receptors, without a change in apparent receptor affinity and with lower levels of the GTP-binding proteins Gs and Gi, visualized by NAD-dependent [32P]ADP ribosylation. The reduction in AP was correlated with a decrease in the steady state level of AP mRNA. RA had no effect on cell proliferation or saturation density. Retinoids thus inhibit the same features that are promoted by glucocorticoids in ROS 17/2.8 cells. These features seem to be subject to coordinate regulation, probably at the pretranslational level.
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PMID:Effects of retinoic acid on alkaline phosphatase messenger ribonucleic acid, catecholamine receptors, and G proteins in ROS 17/2.8 cells. 282 98

We identified the subunits of the stimulatory and inhibitory guanine nucleotide binding proteins (Gs and Gi, respectively) associated with adenylate cyclase in rat osteosarcoma (ROS) cells. Pertussis toxin catalyzed ADP-ribosylation of Gi alpha in ROS cells increased agonist (PTH and isoproterenol)-stimulated, but not basal, cAMP production. The effect of pertussis toxin was dose and time dependent, and slowly reversible (T 1/2 approximately 30 h) during continued culture without toxin. Pertussis toxin treatment of ROS cell lines (17/2.8 and 24/l) with markedly different agonist responsiveness increased agonist-stimulated cAMP production in proportion to the response without toxin treatment. Pertussis toxin treatment further increased cAMP response to PTH in dexamethasone treated cells. We conclude that ROS cells contain functional Gi which modulates agonist-stimulated cAMP formation. Alterations in ROS cAMP responsiveness caused by steroids, and the reduced responsiveness of the 24/1 cell line, however, are unlikely to be due to changes in Gi.
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PMID:The inhibitory guanine nucleotide regulatory protein modulates agonist-stimulated cAMP production in rat osteosarcoma cells. 285 47

Mutations and deletions in mitochondrial DNA (mtDNA) lead to a number of human diseases characterized by neuromuscular degeneration. Accumulation of truncated mtDNA molecules (delta-mtDNA) lacking a specific 4977-bp fragment, the common deletion, leads to three related mtDNA diseases: Pearson's syndrome; Kearns-Sayre syndrome; and chronic progressive external ophthalmoplegia (CPEO). In addition, the proportion of delta-mtDNA present increases with age in a range of tissues. Consequently, there is considerable interest in the effects of the accumulation of delta-mtDNA on cell function. The 4977-bp deletion affects genes encoding 7 polypeptide components of the mitochondrial respiratory chain, and 5 of the 22 tRNAs necessary for mitochondrial protein synthesis. To determine how the accumulation of delta-mtDNA affects oxidative phosphorylation we constructed a series of cybrids by fusing a human osteosarcoma cell line depleted of mtDNA (rho0) with enucleated skin fibroblasts from a CPEO patient. The ensuing cybrids contained 0-86% delta-mtDNA and all had volumes, protein contents, plasma-membrane potentials and mitochondrial contents similar to those of the parental cell line. The bioenergetic consequences of accumulating delta-mtDNA were assessed by measuring the mitochondrial membrane potential, rate of ATP synthesis and ATP/ADP ratio. In cybrids containing less than 50-55% delta-mtDNA, these bioenergetic functions were equivalent to those of cybrids with intact mtDNA. However, once the proportion of delta-mtDNA exceeded this threshold, the mitochondrial membrane potential, rate of ATP synthesis, and cellular ATP/ADP ratio decreased. These bioenergetic deficits will contribute to the cellular pathology associated with the accumulation of delta-mtDNA in the target tissues of patients with mtDNA diseases.
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PMID:Bioenergetic consequences of accumulating the common 4977-bp mitochondrial DNA deletion. 979 19

Spontaneous apoptosis in human osteosarcoma cells was observed to be associated with a marked increase in the intracellular abundance of p53. Immunoprecipitation and immunoblot analysis revealed that, together with a variety of other nuclear proteins, p53 undergoes extensive poly(ADP-ribosyl)ation early during the apoptotic program in these cells. Subsequent degradation of poly(ADP-ribose) (PAR), attached to p53 presumably by PAR glycohydrolase, the only reported enzyme to degrade PAR, was apparent concomitant with the onset of proteolytic processing and activation of caspase-3, caspase-3-mediated cleavage of poly(ADP-ribose) polymerase (PARP), and internucleosomal DNA fragmentation during the later stages of cell death. The decrease in PAR covalently bound to p53 also coincided with the marked induction of expression of the p53-responsive genes bax and Fas. These results suggest that poly(ADP-ribosyl)ation may play a role in the regulation of p53 function and implies a regulatory role for PARP and/or PAR early in apoptosis.
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PMID:Poly(ADP-ribosyl)ation of p53 during apoptosis in human osteosarcoma cells. 1023 7


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