Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Osteosarcoma is the most frequent primitive malignant tumor of the skeletal system and is characterized by an extremely aggressive clinical course that lacks an effective treatment. This study is the first to investigate the anti-cancer effects of a new isoflavone-derived 7-hydroxy-3',4'-benzoisoflavone (HBI) in human osteosarcoma cells. HBI-induced cell apoptosis in human osteosarcoma cell lines. The accumulation of reactive oxygen species (ROS) is a critical mediator in HBI induced cell death. HBI also induced apoptosis signal-regulating kinase 1 (ASK1) dephosphorylation, p38, JNK and p53 phosphorylation. Transfection with ASK1, p38 and JNK small interfering RNA (siRNA) antagonized HBI-induced cell apoptosis. HBI also triggered the mitochondrial apoptotic pathway, as indicated by a change in Bax/Bcl2 ratio. Bax knockdown using a Bax siRNA strategy reduced Bax expression and subsequent cell death. In addition, ASK1, p38 and JNK siRNA reduced HBI-induced p53 phosphorylation and Bax expression. These results suggest that the ROS-ASK1-p38/JNK-p53 and Bax pathway plays a critical role in HBI's anti-cancer effects.
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PMID:The novel isoflavone 7-hydroxy-3',4'-benzoisoflavone induces cell apoptosis in human osteosarcoma cells. 1860 92

Osteosarcoma is characterized by a high malignant and metastatic potential, which points to the need for new therapeutic strategies to prevent cell metastasis. In this study, we show that statin-induced HMG-CoA reductase inhibition reduces cell migration and invasion in human and murine osteosarcoma cells, independently of the genotype. The statin-induced reduction of cell migration and invasion was independent of induction of apoptosis and was geranylgeranylpyrophosphate-dependent. The statin reduced matrix metalloproteinase (MMP) 2, 9, and 14 and TIMP2 expression or activity in invading cells. Forced expression of MMP2 and MMP14 overcame the inhibitory effect of the statin on cell invasion, suggesting a role for these MMPs in invasive potential. We also investigated the mechanisms involved in the reduced MMP2 activity and cell invasion. Inhibition of JNK, but not ERK1/2 signaling, reduced MMP2 activity. Pharmacological or constitutive activation of JNK overcame the reduced MMP2 activity and cell invasion induced by the statin. The statin decreased JNK phosphorylation and c-Jun nuclear translocation, suggesting that HMG-CoA reductase inhibition targets the JNK-c-Jun signaling pathway. We showed that mevalonate or geranylgeranylpyrophosphate treatment prevented the statin-induced reduction in JNK phosphorylation, MMP2 activity, and cell invasion. Forced expression of a constitutively active form of RhoA increased JNK phosphorylation and overcame the inhibitory effect of atorvastatin on MMP2 activity and cell invasion. The data establish a link between RhoA, JNK, c-Jun, and MMP2 activity that is functionally involved in the reduction in osteosarcoma cell invasion by the statin. This suggests a novel strategy targeting RhoA-JNK-c-Jun signaling to reduce osteosarcoma cell tumorigenesis.
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PMID:Blockade of the RhoA-JNK-c-Jun-MMP2 cascade by atorvastatin reduces osteosarcoma cell invasion. 1875 69

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

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

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

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

Ewing sarcoma and osteosarcoma are two aggressive cancers that affect bones and soft tissues in children and adolescents. Despite multimodal therapy, patients with metastatic sarcoma have a poor prognosis, emphasizing a need for more effective treatment. We have shown previously that 2-methoxyestradiol (2-ME), an antitumoral compound, induces apoptosis in Ewing sarcoma cells through c-Jun NH(2)-terminal kinase (JNK) activation. In the present study, we provide evidence that 2-ME elicits macroautophagy, a process that participates in apoptotic responses, in a JNK-dependent manner, in Ewing sarcoma and osteosarcoma cells. We also found that the enhanced activation of JNK by 2-ME is partially regulated by p53, highlighting the relationship of JNK and autophagy to p53 signaling pathway. Furthermore, we showed that 2-ME up-regulates damage-regulated autophagy modulator (DRAM), a p53 target gene, in Ewing sarcoma cells through a mechanism that involves JNK activation. The silencing of DRAM expression reduced both apoptosis and autophagy triggered by 2-ME in Ewing sarcoma and osteosarcoma cells. Our results therefore identify JNK as a novel mediator of DRAM regulation. These findings suggest that 2-ME or other anticancer therapies that increase DRAM expression or function could be used to effectively treat sarcoma patients.
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PMID:c-Jun NH2-terminal kinase activation is essential for DRAM-dependent induction of autophagy and apoptosis in 2-methoxyestradiol-treated Ewing sarcoma cells. 1970 54

Osteosarcoma (OS) is the most common primary malignant bone tumour, mainly afflicting the young. While there has been substantial improvement in treatment of OS with surgery and chemotherapy in the past two decades, this disease remains a significant health problem, warranting efforts to find better therapeutic options. In this study, we examined the RANK/RANKL axis in OS cells, using a RANK-Fc protein to perturb this coupling in an effort to reduce OS cell growth. RANK-Fc suppressed OS cell migration (P < 0.005), invasion ability (P < 0.05), and anchorage-independent ability in collagen-1 gel (P < 0.005) following induction of anoikis and activation of caspase-3. OS cell proliferation was not perturbed by RANK-Fc. The anti-invasion and anti-metastasis capability of RANK-Fc is attributed to reduced extracellular signal-regulated protein kinase (ERK) signaling via RANK-Fc, though activation of NFkappaB, and altered expression of Akt, p38, JNK, and matrix metalloproteinase (MMP)-2 and -9 were ruled out. In vivo, activity of the RANK-Fc against OS cell migration and invasion was confirmed in a model strictly monitoring metastasis. Thus, RANK-Fc, given its ability to directly reduce OS aggression, is a potential drug candidate.
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PMID:RANK-Fc inhibits malignancy via inhibiting ERK activation and evoking caspase-3-mediated anoikis in human osteosarcoma cells. 2038 67

Our previous study demonstrated that 6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline (LJJ-10) possesses potential anticancer activity and exhibits greater antitumor effect than the other quinazoline compounds in human osteogenic sarcoma U-2 OS cells via in vitro screening. In this study, we focused on investigating the anti-metastatic activity and the signaling pathways involved in LJJ-10 action in U-2 OS cells. The results from wound healing and Boyden chamber transwell assays indicated that LJJ-10 exhibited an inhibitory effect on the migration and invasion of U-2 OS cells. LJJ-10 also inhibited matrix metalloproteinase-2 (MMP-2) and MMP-9 enzyme activities and caused a concentration-dependent decrease in protein levels by gelatin zymography assay and Western blot analysis, respectively. Meanwhile, LJJ-10 suppressed MMP-2 and MMP-9 mRNA levels in a concentration-dependent fashion after 12-h exposure in U-2 OS cells. Computational modeling showed that LJJ-10 is bound into the IGF-1R via hydrophobic interactions with Leu975, Val983, Ala1001, Glu1050 and Met1052 with one hydrogen bond between 6-F and Met1052. LJJ-10 reduced the protein levels of p-JNK, p-p38, p-ERK, p-AKT and p-IGFR by Western blotting and these influences are concentration-dependent. Based on these observations, this study suggests that molecular targeting of the insulin-like growth factor-I receptor (IGF-1R) signaling leads to the suppression of downstream MAPK/AKT signaling and downregulation of MMP-2 and -9 RNA levels and protein levels in LJJ-10-treated U-2 OS cells. Therefore, the inhibition of metastasis in human osteosarcoma cells by treatment with this novel agent, LJJ-10 may be a useful chemotherapeutic approach.
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PMID:The novel synthesized 6-fluoro-(3-fluorophenyl)-4-(3-methoxyanilino)quinazoline (LJJ-10) compound exhibits anti-metastatic effects in human osteosarcoma U-2 OS cells through targeting insulin-like growth factor-I receptor. 2166 22

Identification of natural products that have antitumor activity is invaluable to the chemoprevention and therapy of cancer. The embryos of lotus (Nelumbo nucifera) seeds are consumed in beverage in some parts of the world for their presumed health-benefiting effects. In this report we studied the effects of neferine, a major alkaloid component in lotus embryos, on human osteosarcoma cells and the underlying mechanisms. We found that neferine possessed a potent growth-inhibitory effect on human osteosarcoma cells, but not on non-neoplastic human osteoblast cells. The inhibitory effect of neferine on human osteosarcoma cells was largely attributed to cell cycle arrest at G1. The induction of G1 arrest was p21(WAF1/CIP1)-dependent, but was independent of p53 or RB (retinoblastoma-associated protein). The up-regulation of p21 by neferine was due to an increase in the half-life of p21 protein. We examined four kinases that are known to affect the stabilization of p21, and found that p38 MAPK and JNK were activated by neferine. However, only SB203580 (an inhibitor of p38), but not SP600125 (the inhibitor of JNK), can attenuate the up-regulation of p21 in response to neferine. Furthermore, the p21-stabilizing effect of neferine was abolished when p38 was silenced by RNA interference. Finally, we showed that neferine treatment led to an increased phosphorylation of p21 at Ser130 that was dependent on p38. Our results for the first time showed a direct antitumor effect of neferine, suggesting that consumption of neferine may have cancer-preventive and cancer-therapeutic benefit.
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PMID:Neferine, an alkaloid ingredient in lotus seed embryo, inhibits proliferation of human osteosarcoma cells by promoting p38 MAPK-mediated p21 stabilization. 2222 30


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