Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Osteoprotegerin (OPG) is a major regulator of osteoclastogenesis, bone resorption and vascular calcification. OPG is produced by various cell types including mesenchymally derived cells, in particular, osteoblastic cells. Here we show OPG production by osteoblastic cells was stimulated by platelet-derived growth factor (PDGF) in two human osteosarcoma cell lines (MG63, Saos-2), a mouse pre-osteoblastic cell line (MC3T3-E1) and human bone marrow stromal cells (hMSC) by 152%, 197%, 113% and 45% respectively over 24 h. OPG was measured in the cell culture medium by immunoassay. PDGF isoforms AA, BB and AB show similar stimulation of OPG production. Message for OPG was also increased similarly to the increased secretion into the culture medium. Using specific inhibitors of cell signalling we demonstrate that PDGF acts through the PDGF receptor, PKC, PI3K, ERK and P38 and not via NF-kB or JNK. The importance of PDGF in fracture healing suggests a role for OPG production in countering bone resorption during the early phase of this process.
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PMID:Platelet-derived growth factor stimulates osteoprotegerin production in osteoblastic cells. 1881 41

1. It has been shown that the antidepressant desipramine is able to induce increases in [Ca(2+)](i) and cell death in MG63 human osteosacroma cells, but whether apoptosis is involved is unclear. In the present study, the effect of desipramine on apoptosis and the underlying mechanisms were explored. It was demonstrated that desipramine induced cell death in a concentration- and time-dependent manner. 2. Cells treated with 100-800 mmol/L desipramine showed typical apoptotic features, including an increase in sub-diploid nuclei and activation of caspase 3, indicating that these cells underwent apoptosis. Immunoblotting revealed that 100 mmol/L desipramine activated extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). Although pretreatment of cells with 20 mmol/L PD98059 (an ERK inhibitor) or 20 mmol/L SP600125 (an inhibitor of JNK) did not inhibit cell death, the addition of 20 mmol/L SB203580 (a p38 MAPK inhibitor) partially rescued cells from apoptosis. Desipramine-induced caspase 3 activation required p38 MAPK activation. 3. Pretreatment of cells with BAPTA/AM (20 mmol/L) to prevent desipramine-induced increases in [Ca(2+)](i) did not protect cells from death. 4. The results of the present study suggest that, in MG63 human osteosarcoma cells, desipramine causes Ca(2+)-independent apoptosis by inducing p38 MAPK-associated activation of caspase 3.
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PMID:Desipramine-induced Ca-independent apoptosis in Mg63 human osteosarcoma cells: dependence on P38 mitogen-activated protein kinase-regulated activation of caspase 3. 1898 28

The histone deacetylase inhibitor depsipeptide [(1S,4S,7Z,10S, 16E,21R)-7-ethylidene-4,21-bis(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19, 22-pentone] (FK228) has attracted a great deal of interest because of its antiproliferative and apoptotic properties in various malignancies. Histone deacetylase inhibitors induce the expression of the multidrug resistance transporter P-glycoprotein (P-gp), and FK228 is a known P-gp substrate. Thus, FK228 seems to induce its own mechanism of drug resistance by up-regulating P-gp. The goal of this study was to establish human FK228-resistant osteosarcoma cell lines and to investigate whether there are mechanisms of FK228 resistance in addition to P-gp up-regulation. After 72 h in culture, the 50% inhibitory concentrations (IC(50)) of FK228 were 4.8 and 991 nM in HOS and HOS/FK8 cells, respectively, and 3.6 and 1420 nM in U2OS and U2OS/FK11 cells, respectively. Increased histone H3 acetylation was observed in FK228-resistant cell lines after a 1-h treatment with 10 nM FK228. Unlike in parental cells, significant P-gp overexpression was detected in FK228-resistant cells, and 10 nM FK228 treatment activated the mitogen-activated protein kinase (MAPK) pathway but did not induce Fas ligand (FasL) up-regulation or c-FLIP down-regulation. However, treatment of FK228-resistant cells with a combination of FK228 and mitogen-activated protein kinase kinase (MEK) inhibitors induced apoptosis, up-regulated FasL, and down-regulated c-FLIP. The expression and function of P-gp were unaltered by treatment with MEK inhibitors. These results indicate that the FK228 resistance of osteosarcoma cells is related to P-gp overexpression and MAPK pathway activation by FK228. MEK or P-gp inhibitors may be useful in overcoming this resistance.
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PMID:Involvement of extracellular signal-regulated kinase activation in human osteosarcoma cell resistance to the histone deacetylase inhibitor FK228 [(1S,4S,7Z,10S,16E,21R)-7-ethylidene-4,21-bis(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone]. 1907 9

A well-characterized murine osteosarcoma model for metastasis and invasion was used in this study to determine the role of AP-1 in the progression of this disease. We analyzed K12 and K7M2 cells, two clonally related murine osteosarcoma cell lines that have been characterized as low metastatic or high metastatic, respectively, for AP-1 components and activity. AP-1 DNA binding was similar between the two cell lines; however AP-1 transcriptional activity was enhanced by 3- to 5-fold in K7M2 cells relative to that in K12 cells. The AP-1 complexes in K12 and K7M2 cells was composed primarily of cJun, JunD, FosB, Fra1, and Fra2, with the contribution of individual components in the complex varying between the two cell lines. In addition, an increase in phosphorylated cJun, JNK activity, and phosphorylated ERK1/2 was associated with the more metastatic osteosarcoma phenotype. The significance of AP-1 activation was confirmed by conditional expression of TAM67, a dominant negative mutant of cJun. Under conditions where TAM67 inhibited AP-1 activity in K7M2 cells, migration and invasion potential was significantly blocked. Tam67 expression in aggressive osteosarcoma cells decreased long-term in vivo experimental metastasis and increased survival of mice. This study shows that differences in metastatic activity can be due to AP-1 activation. The inhibition of AP-1 activity may serve as a therapeutic tool in the management of osteosarcoma.
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PMID:Inhibition of AP-1 transcriptional activity blocks the migration, invasion, and experimental metastasis of murine osteosarcoma. 1907 13

Osteosarcoma is highly resistant to current chemotherapy regimens. Novel therapeutic approaches, potentially involving targeting of specific survival pathways, are needed. We used 17-AAG to inhibit Hsp90 and rapamycin to inhibit mTOR, in the osteosarcoma cell lines, HOS and KHOS/NP. HOS and KHOS cells were treated for 24 and 48 h with 17-AAG or rapamycin and studied drug-induced apoptosis, cell cycle, mitochondrial membrane potential and levels of reduced glutathione (GSH), dephosphorylation of signal transduction proteins in the Akt/MAP kinase pathway and mTOR signaling. 17-AAG was a potent inducer of apoptosis, involving effective depletion of GSH and mitochondrial membrane (MM) depolarization, strong activation of caspase-8 and -9 and release of AIF from mitochondria to the cytosol. Furthermore, 17-AAG down-regulated pAkt, p44Erk, p-mTOR, p70S6, TSC1/2 and pGSK-3beta. Treatment with 17-AAG also caused down-regulation of cyclin D1, GADD45a, GADD34 and pCdc2 and upregulation of cyclin B1 and mitotic block. A decrease in Hsp90 and increase in Hsp70 and Hsp70 C-terminal fragments were also observed. Rapamycin was a less potent inducer of apoptosis, involving a small decrease in GSH and MM potential with no activation of caspases or release of AIF. Rapamycin strongly inhibited cell growth with an increase in G1 and a decrease in S-phase of the cell cycle concomitant with down-regulation of cyclin D1. Rapamycin also down-regulated the activity of p70S6, pAkt and p-mTOR, but had no effect on pGSK-3beta, p44Erk, pCdc2, TSC1/2 or Hsp70 or Hsp90. We conclude that Hsp90 inhibition merits further study in the therapy of osteosarcoma.
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PMID:Targeted therapy of human osteosarcoma with 17AAG or rapamycin: characterization of induced apoptosis and inhibition of mTOR and Akt/MAPK/Wnt pathways. 1914 92

Arthritis is one of the most prevalent chronic inflammatory diseases, and it is characterized by structural and biochemical changes in major tissues of the joint, including degradation of the cartilage matrix, insufficient synthesis of extracellular matrix (ECM). Ecklonia cava (EC) is a member of the family of Laminariaceae, which is an edible marine brown alga with various bioactivities. In this study of the methanol extract of brown alga EC, the dieckol (1) and 1-(3',5'-dihydroxyphenoxy)-7-(2'',4'',6''-trihydroxyphenoxy) 2,4,9-trihydroxydibenzo-1,4,-dioxin (2) were isolated and characterized by NMR techniques with high yield. Phlorotannin derivatives (1, 2) promoted osteosarcoma differentiation by increasing alkaline phosphatase (ALP) activity, mineralization, total protein and collagen synthesis in human osteosarcoma cell (MG-63 cells), respectively. Furthermore, these phlorotannin derivatives (1, 2) inhibited mRNA gene and protein levels of matrix metalloproteinase (MMP-1, MMP-3, and MMP-13), iNOS and COX-2 in casein zymography, Western blot and reverse transcriptase-polymerase chain reaction (RT-PCR) assays. In addition, it was observed that the phlorotannins inhibited phosphorylation of JNK and p38 MAPK in human osteosarcoma cell. These results suggested the phlorotannin derivatives (1, 2) could promote cell differentiation, attenuate MMP-1, MMP-3, MMP-13 expressions, and inflammatory response via MAPK pathway in chronic articular diseases.
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PMID:Differentiation of human osteosarcoma cells by isolated phlorotannins is subtly linked to COX-2, iNOS, MMPs, and MAPK signaling: implication for chronic articular disease. 1933 Aug 80

CTRP3/cartducin, a novel secretory protein, is a member of the C1q and tumor necrosis factor (TNF)-related protein (CTRP) superfamily, and plays important roles in regulating both embryonic cartilage development and postnatal longitudinal bone growth. CTRP3/cartducin is expressed in human osteosarcomas. We hypothesized that CTRP3/cartducin might have a role in osteosarcoma tumor growth and metastasis. Murine osteosarcoma cell lines, NHOS and LM8, were used as a model. RT-PCR analysis showed that the mRNA level of CTRP3/cartducin was increased in these two murine osteosarcoma cell lines compared with its level in normal murine osteoblast MC3T3-E1 cells. Western blot analysis showed that the protein level of CTRP3/cartducin was also increased in these two osteosarcoma cell lines. Stimulation of NHOS and LM8 cells by CTRP3/cartducin promoted tumor cell growth but not migration in vitro. Further, CTRP3/cartducin stimulation led to the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) in these two osteosarcoma cell lines. MAPK/ERK kinase 1/2 (MEK1/2) inhibitor, U0126, blocked CTRP3/cartducin-induced cell proliferation. These results suggest that CTRP3/cartducin expression may play a role in osteosarcoma tumor growth associated with activation of the ERK1/2 signaling pathway.
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PMID:Elevated expression of CTRP3/cartducin contributes to promotion of osteosarcoma cell proliferation. 1942 26

Osteosarcoma is characterized by a high malignant and metastatic potential. The chemokine stromal-derived factor-1alpha (SDF-1alpha) and its receptor, CXCR4, play a crucial role in adhesion and migration of human cancer cells. Integrins are the major adhesive molecules in mammalian cells, and has been associated with metastasis of cancer cells. Here, we found that human osteosarcoma cell lines had significant expression of SDF-1 and CXCR4 (SDF-1 receptor). Treatment of osteosarcoma cells with SDF-1alpha increased the migration and cell surface expression of alphavbeta3 integrin. CXCR4-neutralizing antibody, CXCR4 specific inhibitor (AMD3100) or small interfering RNA against CXCR4 inhibited the SDF-1alpha-induced increase the migration and integrin expression of osteosarcoma cells. Pretreated of osteosarcoma cells with MAPK kinase (MEK) inhibitor PD98059 inhibited the SDF-1alpha-mediated migration and integrin expression. Stimulation of cells with SDF-1alpha increased the phosphorylation of MEK and extracellular signal-regulating kinase (ERK). In addition, NF-kappaB inhibitor (PDTC) or IkappaB protease inhibitor (TPCK) also inhibited SDF-1alpha-mediated cell migration and integrin up-regulation. Stimulation of cells with SDF-1alpha induced IkappaB kinase (IKKalpha/beta) phosphorylation, IkappaB phosphorylation, p65 Ser(536) phosphorylation, and kappaB-luciferase activity. Furthermore, the SDF-1alpha-mediated increasing kappaB-luciferase activity was inhibited by AMD3100, PD98059, PDTC and TPCK or MEK1, ERK2, IKKalpha and IKKbeta mutants. Taken together, these results suggest that the SDF-1alpha acts through CXCR4 to activate MEK and ERK, which in turn activates IKKalpha/beta and NF-kappaB, resulting in the activations of alphavbeta3 integrins and contributing the migration of human osteosarcoma cells.
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PMID:Stromal cell-derived factor-1/CXCR4 enhanced motility of human osteosarcoma cells involves MEK1/2, ERK and NF-kappaB-dependent pathways. 1949 72

This study examined the effect of ketoconazole on viability, apoptosis, mitogen-activated protein kinases (MAPKs) and Ca(2+) levels in MG63 osteosarcoma cells. Ketoconazole at 20-200 microM decreased cell viability via apoptosis as demonstrated by propidium iodide staining and activation of caspase-3. Immunoblotting suggested that ketoconazole induced phosphorylation of ERK and JNK, but not p38, MAPKs. Ketoconazole-induced cell death and apoptosis were partially reversed by the selective JNK inhibitor SP600125, but not by the selective ERK inhibitor PD98059, suggesting that ketoconazole's cytotoxic action was via JNK, but not via ERK and p38 MAPKs. Ketoconazole at a concentration of 100 microM induced [Ca(2+)](i) increases. Chelation of intracellular Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) totally inhibited ketoconazole-induced [Ca(2+)](i) increases without reversing ketoconazole-induced cell death. Collectively, in MG63 cells, ketoconazole induced cell death and apoptosis via evoking JNK phosphorylation in a Ca(2+)-independent manner.
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PMID:Ketoconazole-induced JNK phosphorylation and subsequent cell death via apoptosis in human osteosarcoma cells. 1963 32

For the control of tumor metastasis it is important to identify chemical compounds with antimigratory potency. Agents acting against single cell and cluster type migration are necessary for successful antimetastatic therapy. In the present study, the migration of HT-1080 fibrosarcoma cells and OSCORT osteosarcoma cells was compared in a Boyden chamber and in an extracellular matrix (ECM)-based three-dimensional cell culture (3-DCC) model system. The Boyden chamber offers a model of single tumor cell migration, whereas the 3-DCC model system demonstrates invasive growth in the form of a cluster. Since PD98059 (MEK inhibitor) exclusively reduced migration in the 3-DCC model, it may be plausible that the ERK/MAPK signaling pathway is essential for cluster type migration. Interestingly, single cell migration was stimulated upon blocking phosphatidylinositol 3-kinase (PI3K) and also p38-MAPK by treatment with LY294002 and SB203580 respectively. A remarkable reduction of single cell migration was observed following treatment with okadaic acid, a phosphatase 1 (PP1) and 2A (PP2A) inhibitor, which was rather intriguing. This study provided evidence that certain cytotoxic/cytostatic agents at appropriate concentrations were able to preferentially inhibit certain types of migration relative to cell proliferation. Single cell migration was selectively inhibited by taxol at very low subtoxic concentration, whereas 5-hexyl-2'-deoxyuridine (HUdR) exclusively inhibited the cluster type of migration. The borrelidin compound was able to inhibit both types of tumor cell migration, but single tumor cell migration was much less affected. It is interesting that migration was more reduced than proliferation by borrelidin, especially at the advanced growth stage. Taxol is recommended as an agent acting against single cell migration, as well as HUdR and borrelidin as leading compounds for developing antimetastatic drugs against cluster type migration.
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PMID:Differential inhibition of single and cluster type tumor cell migration. 1966 4


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