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)

p16(INK4a) (hereafter referred to as p16), a major cyclin-dependent kinase (CDK) inhibitor, is the product of a tumor-suppressor gene that has been found inactivated in different cancer types. In the present study, we sought to investigate the role of p16 in apoptosis induced by ultraviolet light (the most important etiological cause of skin cancer) and cisplatin (an anticancer DNA damaging agent). It is clearly shown that p16-compromised osteosarcoma U2OS cell line and p16-/- mouse embryo fibroblasts are sensitive to UV-induced apoptosis, as compared to their respective isogenic p16-expressing cells (EH1, EH2) and p16 +/+, indicating that p16 protects cells from undergoing apoptosis in response to UV light. Importantly, this reduction in UV-mediated apoptosis was associated with downregulation of the proapoptotic Bax protein, with no effect on Bcl-2 expression, suggesting that this antiapoptotic role of p16 is mediated via the intrinsic-mitochondrial pathway. On the other hand, p16 sensitized cells to cisplatin-mediated apoptosis through Bcl-2 decline. Interestingly, only proliferating but not G1-arrested EH1 cells underwent apoptosis in response to the anticancer drug. These novel findings provide further insight into the role of p16 in carcinogenesis, and has potential implications for future therapy strategies.
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PMID:The tumor suppressor p16(INK4a) gene is a regulator of apoptosis induced by ultraviolet light and cisplatin. 1471 25

In our previous study, we examined reactive oxygen species (ROS) formation in T lymphocytes following 5 Gy irradiation. We found that ROS formation occurred immediately after irradiation, continued for several hours, and resulted in oxidative DNA damage. Therefore, the origin of the hyper-radiosensitivity of T lymphocytes seemed to be the high production of ROS in the mitochondrial DNA following irradiation. In the succeeding study, we examined radiation-induced ROS formation, oxidative DNA damage, early apoptotic changes, and mitochondrial membrane dysfunction in the human osteosarcoma cell line HS-Os-1. We found that ROS formation and oxidative DNA damage were actually scarcely seen after irradiation of up to 30 Gy in these cells, that mitochondrial membrane potential was preserved, and that apoptotic changes were not demonstrated despite the relatively high-dose irradiation of 30 Gy. In the present study, we examined the immunocytochemical characteristics of the apoptotic-resistance of the HS-Os-1 cell line against irradiation in order to clarify its possible implications regarding radiosensitivity. The results showed that these cells lack P53 and Bax protein expression, and strong peroxidase activity was confirmed in the nuclei of the cells. Moreover, SODII (manganese superoxide dismutase II) protein expression was gradually increased in spite of irradiation of up to 30 Gy. Therefore, it is concluded that HS-Os-1 cells are originally apoptotic-resistant and that the cells possess a strong ability to scavenge for free radicals. To convert these cells to a state of apoptotic-susceptibility, a powerful oxidant such as hydrogen peroxide might exert such an effect in terms of the production of hydroxyl radicals in lysosomes in the cells as shown in our previous studies. The origin of the radioresistance of the human osteosarcoma cell line HS-Os-1 is considered to to be low degree of ROS formation following irradiation, reflecting the strong scavenging ability of these cells for free radicals including hydroxyl radicals.
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PMID:Immunocytochemical characteristics of human osteosarcoma cell line HS-Os-1: possible implication in apoptotic resistance against irradiation. 1528 91

p33ING1b can stimulate cell cycle arrest, DNA repair, apoptosis and chemosensitivity. The actions of p33ING1b involve p53-dependent and p53-independent mechanisms. To investigate if the p33ING1b isoform is involved in the chemosensitivity of osteosarcoma cells, p33ING1b was overexpressed in p53+/+ U2OS cells or p53-mutant MG63 cells, and then cell growth arrest and apoptosis were assessed after treatment with taxol. The results showed that p33ING1b markedly increased taxol-induced growth inhibition and apoptosis in p53+/+ U2OS cells, but not in p53-mutant MG63 cells. Moreover, ectopic expression of p33ING1b could obviously upregulate p53, p21WAF1 and bax protein levels and activate caspase-3 in taxol-treated U2OS cells. Taken together, our data demonstrate that p33ING1b enhances taxol-induced apoptosis through p53-dependent pathway in human osteosarcoma cells. p33ING1b may be an important marker and/or therapeutic target in the prevention and treatment of osteosarcoma.
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PMID:The tumor suppressor p33ING1b enhances taxol-induced apoptosis by p53-dependent pathway in human osteosarcoma U2OS cells. 1571 Nov 22

To elucidate the possible effect of NFkappaB on radioresistance, we used the osteosarcoma cell line Saos2, stably expressing the NFkappaB constitutive inhibitor, mIkappaB (Saos2-mIkappaB) or stably transfected with the empty vector (Saos2-EV). Ionizing radiation induced "intrinsic" apoptosis in Saos2-mIkappaB cells but not in Saos2-EV control cells, with intact NFkappaB activity. We find as expected, that this NFkappaB activity was enhanced following irradiation in the Saos2-EV control cells. On the other hand, inhibition of NFkappaB signaling in Saos2-mIkappaB cells led to the upregulation of the pro-apoptotic systems, such as Bax protein and c-Jun N-terminal Kinase (JNK)/c-Jun/AP1 signaling. Inhibition of NFkappaB resulted in decreased expression of the DNA damage protein GADD45beta, a known inhibitor of JNK. Subsequently, JNK activation of c-Jun/AP-1 proteins increased radiation-induced apoptosis in these mutants. Radiation-induced apoptosis in Saos2-mIkappaB cells was inhibited by the JNK specific inhibitor SP600125 as well as by Bcl-2 over-expression. Furthermore, release of cytochrome-c from mitochondria was increased and caspase-9 and -3 were activated following irradiation in Saos2-mIkappaB cells. Antisense inhibition of GADD45beta in Saos2-EV cells significantly enhanced apoptosis following irradiation. Our results demonstrate that radioresistance of Saos2 osteosarcoma cells is due to NFkappaB-mediated inhibition of JNK. Our study brings new insight into the mechanisms underlying radiation-induced apoptosis of osteosarcoma, and may lead to development of new therapeutic strategies against osteosarcoma.
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PMID:Increased radiation-induced apoptosis of Saos2 cells via inhibition of NFkappaB: a role for c-Jun N-terminal kinase. 1616 36

p33ING1b induces cell cycle arrest and stimulates DNA repair, apoptosis and chemosensitivity. The magnitude of some p33ING1b effects may be due to activation of the tumor suppressor p53. To investigate if the p33ING1b protein affected chemosensitivity of osteosarcoma cells, we overexpressed p33ING1b in p53+/+ U2OS cells or in p53-mutant MG63 cells, and then assessed for growth arrest and apoptosis after treatment with etoposide. p33ING1b increased etoposide-induced growth inhibition and apoptosis to a much greater degree in p53+/+ U2OS cells than in p53-mutant MG63 cells. Moreover, ectopic expression of p33ING1b markedly upregulated p53, p21WAF1 and bax protein levels and activated caspase-3 protein kinase in etoposide-treated U2OS cells. Together, our data indicate that p33ING1b prominently enhances etoposide-induced apoptosis through p53-dependent pathways in human osteosarcoma cells. p33ING1b may be an important marker and/or therapeutic target in the prevention and treatment of metastatic osteosarcoma.
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PMID:The p33ING1b tumor suppressor cooperates with p53 to induce apoptosis in response to etoposide in human osteosarcoma cells. 1632 12

The growth inhibitory effect of a mixture of t,t conjugated linoleic acid isomers (t,t CLA) was investigated in the human osteosarcoma cell MG-63, with references to c9,t11 and t10,c12 CLA isomers. The t,t CLA effectively induced a cytotoxic effect in a time-dependent (0 to 6 d) and concentration-dependent (0 to 40 microM) manner, as compared to the reference and control treatments. The apoptosis and cell cycle related parameters were measured on the cells treated with 40 microM t,t CLA for 4 d. Flow cytometric analysis revealed that the t,t CLA treatment effectively increased the proportion of apoptotic cells with a low DNA content (sub G0/G1) and a marked loss of cells from the G0/G1 phase of the cell cycle, relative to other treatments. The occurrence of the characteristic morphological changes and DNA fragmentation confirmed the apoptosis. The level of Bax protein was increased, whereas the Bcl-2 expression was reduced. In addition, cytochrome c was released from the mitochondria into the cytosol, and the activation of caspase-3 led to the cleavage of poly (ADP-ribose) polymerase (PARP). Moreover, the composition of linoleic and arachidonic acids in membrane was decreased by increase in t,t CLA. These findings suggest that t,t CLA incorporation in membrane activates a mitochondria-mediated apoptosis pathway that can enhance the antiproliferative effect of t,t CLA in the osteosarcoma cells.
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PMID:Growth inhibition of osteosarcoma cell MG-63 by a mixture of trans,trans conjugated linoleic acid isomers: possible mechanistic actions. 1821 79

Synthetic triterpenoids, such as 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO) and its derivatives, are an extremely potent class of new anti-cancer therapeutic agents, characterized by high anti-tumor potency and low toxicity to normal tissues. This report is the first to investigate the effects of C-28 derivatives of CDDO on 22 pediatric solid tumor cell lines, including neuroblastoma, rhabdomyosarcoma, osteosarcoma, and Ewing's sarcoma. We determined IC(50)s in the range of 5-170 nM for inhibition of colony formation and DNA synthesis, and 110-630 nM for metabolic cell death and decrease in cell number, using the C-28 CDDO analogs, CDDO methyl ester (CDDO-Me), CDDO imidazolide (CDDO-Im), CDDO ethyl amide (CDDO-EA), CDDO trifluoroethyl amide (CDDO-TFEA), and CDDO diethylamide (CDDO-DE). After treatment of human neuroblastoma cells with CDDO-Me, cell cycle studies show depletion of the S-phase, while apoptosis studies show conformational activation and mitochondrial translocation of Bax protein, as well as activation of caspases -3 and -8. These data demonstrate the potential utility of CDDO analogs as promising novel therapeutic agents for high-risk pediatric solid tumors.
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PMID:Human neuroblastoma cells rapidly enter cell cycle arrest and apoptosis following exposure to C-28 derivatives of the synthetic triterpenoid CDDO. 1837 97

CWC-8 is a new synthesized novel 2-phenyl-4-quinolone compound in our laboratory which has demonstrated potential antitumor activity. In this study, we have defined the viability inhibition and apoptotic mechanisms of CWC-8 on human osteogenic sarcoma U-2 OS cells. According to the MTT assay, the cell viability was inhibited by CWC-8 in a dose- and time-dependent manner, with an IC(50) of 4.97+/-0.24 microM. CWC-8 treatment induced G(2)/M arrest and apoptosis in U-2 OS cells by cell cycle and flow cytometry analysis. It also profoundly caused a decrease in polymerized tubulin levels by in vitro tubulin polymerization assay which indicated that the microtubular cytoskeleton appears to be one of the cellular targets in response to CWC-8. Western blotting and CDK1 kinase assay showed that CWC-8 treatment caused a time-dependent increase of Cyclin B and CDK1 protein levels and activity during G(2)/M arrest. CWC-8 treatment also caused a time-dependent increase in Fas/CD95, FADD, cytosolic cytochrome c, caspase-8/-9/-3 active form, Apaf-1, AIF, Bax protein levels, and decrease in Bcl-2 protein level. CWC-8 also promoted caspase-8/-9 and -3 activities; however, pretreatment of cells with pan-caspase, caspase-8/-9 and -3 inhibitors led to reduced cell growth inhibition action. Taken together, these findings show CWC-8 could be a potential candidate for cancer therapy.
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PMID:Induction of mitotic arrest and apoptosis by a novel synthetic quinolone analogue, CWC-8, via intrinsic and extrinsic apoptotic pathways in human osteogenic sarcoma U-2 OS cells. 1966 27

beta-Ionone is a constituent of vegetables and fruits, and can induce apoptosis in some types of malignant cells. However, the mechanism of apoptosis in osteosarcoma (U2os) cells is currently unclear. In this study, we determined whether beta-ionone can induce apoptosis in U2os cells in vitro and which signal pathway(s) is involved. We found that beta-ionone inhibited cell proliferation in U2os cells in a concentration- and time-dependent manner and caused cell cycle arrest at the G1-S phase. TUNEL assay, DNA ladder and assessment of Caspase 3 activity showed that apoptosis was the determinant in the effects of beta-ionone. Furthermore, Expression of the p53 protein increased in a concentration-dependent and time-dependent manner according to immunocytochemistry and immunoblotting after beta-ionone treatment. In addition, beta-ionone upregulated Bax protein and downregulated Bcl2 protein which led to Bax translocation and cytochrome c release, subsequently activated Caspase 3, thus resulting in apoptosis. In summary, these data suggested that beta-ionone induced apoptosis in a concentration-dependent manner in U2os cells via a p53-dependent mitochondrial pathway.
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PMID:beta-Ionone-induced apoptosis in human osteosarcoma (U2os) cells occurs via a p53-dependent signaling pathway. 1975 79

Osteosarcoma is the most common type of solid bone cancer, which is the second leading cause of cancer-related death. Hypoxia is an ordinary phenomenon in solid tumor tissues and can induce cell apoptosis but the specific molecular mechanism remains unclear. In this study, we explored the effect and the molecular mechanism of Transglutaminase 2 (TG2) on cell apoptosis in osteosarcoma U2OS cells under hypoxia. We found the enzymatic activity of TG2 is significantly increased and the expression of TG2 is remarkably up-regulated under hypoxia condition. Cell apoptotic rate is markedly increased upon knockdown of TG2 by siRNA under hypoxia. We further investigated the mechanism of cell apoptosis and found Bax protein is significantly increased after depletion of TG2 under hypoxia. Moreover, our data also show that cytochrome C (Cyt C) is significantly increased in cytoplasm and markedly decreased in mitochondria of U2OS cells after depletion of TG2 under hypoxia. Our results suggest that TG2 can inhibit tumor cell apoptosis through down-regulation of Bax and prevention of release Cyt C from mitochondria into cytoplasm.
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PMID:Transglutaminase-2 is Involved in Cell Apoptosis of Osteosarcoma Cell Line U2OS Under Hypoxia Condition. 2556 Dec 82


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