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

Sulforaphane (SFN), a naturally occurring isothiocyanate, is an attractive agent due to its potent anticancer effects. SFN suppresses the proliferation of various cancer cells in vitro and in vivo. In this study, we report that SFN inhibited the proliferation of cultured murine osteosarcoma LM8 cells. Twenty micromolar SFN completely inhibited the growth of LM8 cells and caused G2/M-phase arrest. SFN induced the expression of p21(WAF1/CIP1) protein causing the cell cycle arrest in a dose-dependent manner. SFN induced apoptosis which was characterized by the appearance of cells with sub-G1 DNA content and the cleavage and activation of caspase-3. We showed that SFN induced the growth arrest and up-regulated the expression of p21(WAF1/CIP1) protein in a p53-independent manner in human osteosarcoma MG63 cells. We found that intraperitoneal administration of SFN (1 or 2 mg, 5 times/week) significantly inhibited the growth of LM8 xenografts to <30% of the controls in a preclinical animal model without causing any toxicity. In osteosarcoma cells, our findings provide in vivo evidence for the efficacy of SFN against the advanced growth of tumor. We showed that SFN induces cell cycle arrest and apoptosis in osteosarcoma cells and inhibits tumor xenograft growth. Furthermore, SFN is a potent inducer of p21(WAF1/CIP1) in osteosarcoma cells. These results raise the possibility that SFN may be a promising candidate for molecular-targeting chemotherapy against osteosarcoma.
 ...
PMID:Sulforaphane induces cell cycle arrest and apoptosis in murine osteosarcoma cells in vitro and inhibits tumor growth in vivo. 1791 83

p53 regulates apoptosis and the cell cycle through actions in the nucleus and cytoplasm. Altering the subcellular localization of p53 can alter its biological function. Therefore, small molecules that change the localization of p53 would be useful chemical probes to understand the influence of subcellular localization on the function of p53. To identify such molecules, a high-content screen for compounds that increased the localization of p53 to the nucleus or cytoplasm was developed, automated, and conducted. With this image-based assay, we identified ellipticine that increased the nuclear localization of GFP-mutant p53 protein but not GFP alone in Saos-2 osteosarcoma cells. In addition, ellipticine increased the nuclear localization of endogenous p53 in HCT116 colon cancer cells with a resultant increase in the transactivation of the p21 promoter. Increased nuclear p53 after ellipticine treatment was not associated with an increase in DNA double stranded breaks, indicating that ellipticine shifts p53 to the nucleus through a mechanism independent of DNA damage. Thus, a chemical biology approach has identified a molecule that shifts the localization of p53 and enhances its nuclear activity.
 ...
PMID:A high-content chemical screen identifies ellipticine as a modulator of p53 nuclear localization. 1818 Oct 20

Interstitial flow in and around tumor tissue affects the mechanical microenvironment to modulate tumor cell growth and metastasis. We investigated the roles of flow-induced shear stress in modulating cell cycle distribution in four tumor cell lines and the underlying mechanisms. In all four cell lines, incubation under static conditions for 24 or 48 h led to G(0)/G(1) arrest; in contrast, shear stress (12 dynes/cm(2)) induced G(2)/M arrest. The molecular basis of the shear effect was analyzed, and the presentation on molecular mechanism is focused on human MG63 osteosarcoma cells. Shear stress induced increased expressions of cyclin B1 and p21(CIP1) and decreased expressions of cyclins A, D1, and E, cyclin-dependent protein kinases (Cdk)-1, -2, -4, and -6, and p27(KIP1) as well as a decrease in Cdk1 activity. Using specific antibodies and small interfering RNA, we found that the shear-induced G(2)/M arrest and corresponding changes in G(2)/M regulatory protein expression and activity were mediated by alpha(v)beta(3) and beta(1) integrins through bone morphogenetic protein receptor type IA-specific Smad1 and Smad5. Shear stress also down-regulated runt-related transcription factor 2 (Runx2) binding activity and osteocalcin and alkaline phosphatase expressions in MG63 cells; these responses were mediated by alpha(v)beta(3) and beta(1) integrins through Smad5. Our findings provide insights into the mechanism by which shear stress induces G(2)/M arrest in tumor cells and inhibits cell differentiation and demonstrate the importance of mechanical microenvironment in modulating molecular signaling, gene expression, cell cycle, and functions in tumor cells.
 ...
PMID:Tumor cell cycle arrest induced by shear stress: Roles of integrins and Smad. 1831 Mar 19

2-Methoxyestradiol (2-ME), a naturally occurring mammalian metabolite of 17beta-Estradiol (E2), induces cell death in osteosarcoma cells. To further understand the molecular mechanisms of action, we have investigated cell cycle progression in 2-ME-treated human osteosarcoma (MG63, SaOS-2 and LM7 [corrected]) cells. At 5 microM, 2-ME induced growth arrest by inducing a block in cell cycle; 2-ME-treatment resulted in 2-fold increases in G1 phase cells and a decrease in S phase cells in MG63 and SaOS-2 osteosarcoma cell lines, compared to the appropriate vehicle controls. 2-ME-treatment induced a threefold increase in the G2 phase in LM7 [corrected] osteosarcoma cells. The results demonstrated steroid specificity, as the tumorigenic metabolite, 16alpha-hydroxyestradiol (16-OHE), did not have any effect on cell cycle progression in osteosarcoma cells. The cell cycle arrest coincided with an increase in expression of the cell cycle markers p21, p27 and p53 proteins in 2-ME-treated osteosarcoma cells. Also, MG63 cells, transiently transfected with cDNA for a 'loss of function mutant' RNA-dependent protein kinase (PKR) protein, were resistant to 2-ME-induced cell cycle arrest. These results suggest that 2-ME works in concert with factors regulating cell cycle progression, and cell cycle arrest precedes cell death in 2-ME-treated osteosarcoma cells.
 ...
PMID:2-methoxyestradiol-induced cell death in osteosarcoma cells is preceded by cell cycle arrest. 1838 13

Decorin is an established natural oncosuppressive factor whose action is being studied in detail. Recently, decorin gene therapy formulations using adenoviral vectors have been shown in several animal models with very promising results. The present study describes the first exception to the established oncosuppression model using human osteosarcoma cells. MG-63 osteosarcoma cells were found to constitutively produce decorin, and furthermore, to be resistant to decorin-induced growth arrest. On the contrary, decorin seemed to be beneficial to osteosarcoma cells because it was necessary for MG-63 cell migration and acted as a mediator, counteracting the transforming growth factor-beta2-induced cytostatic function. Efforts to determine how MG-63 cells could overcome the decorin-induced cytostatic effect established that decorin in MG-63 cells does not induce p21 expression nor does it cause protracted retraction and inactivation of the epidermal growth factor receptor. Conversely, epidermal growth factor receptor seemed to be overexpressed and continuously phosphorylated. In view of the proposed design of decorin-based anticancer therapeutic strategies, our study provides new data on pathways that cancer cells might employ to overcome the established decorin-induced growth suppression.
 ...
PMID:Decorin-induced growth inhibition is overcome through protracted expression and activation of epidermal growth factor receptors in osteosarcoma cells. 1850 23

Osteosarcoma is a primary malignant tumor of bone arising from primitive bone-forming mesenchymal cells and accounts for approximately 60% of malignant bone tumors. Our comparative genomic hybridization (CGH) studies have identified frequent amplification at 6p12-p21, 12q13-q15, and 17p11.2 in osteosarcoma. Of these amplified regions, 6p12-p21 is particularly interesting because of its association with progression and poor prognosis in patients with osteosarcoma. In an attempt to identify aberrantly expressed gene(s) mapping to the 6p12-p21 amplicon, a region-specific array was generated using 108 overlapping BAC and P1 clones covering a 28.8-Mb region at 0.26-Mb intervals. Based on array CGH analysis, the 6p amplicon was refined to 7.9 Mb between the clones RP11-91E11 and RP1-244F2 and 10 amplified clones, with possible target genes, were identified. To study the expression pattern of the target genes from the hotspot amplicon and known candidate genes from 6p12-21, we did quantitative reverse transcription-PCR analysis of MAPK14, MAPK13, CDKN1A, PIM1, MDGA1, BTB9, DNAH8, CCND3, PTK7, CDC5L, and RUNX2 on osteosarcoma patient samples and seven cell lines. The combined array CGH and quantitative reverse transcription-PCR analysis identified amplification and overexpression of CDC5L, CCND3, and RUNX2. We screened these three genes for protein expression by Western blotting and immunohistochemistry and detected overexpression of CDC5L. Furthermore, we used an in vivo assay to show that CDC5L possesses potential oncogenic activity. These results indicate that CDC5L, a cell cycle regulator important for the G2-M transition, is the most likely candidate oncogene for the 6p12-p21 amplicon found in osteosarcoma.
 ...
PMID:Cell cycle regulator gene CDC5L, a potential target for 6p12-p21 amplicon in osteosarcoma. 1856 98

Infection by the human T-cell leukemia virus type 1 (HTLV-1) is thought to cause dysregulated T-cell proliferation, which in turn leads to adult T-cell leukemia/lymphoma. Early cellular changes after HTLV-1 infection have been difficult to study due to the poorly infectious nature of HTLV-1 and the need for cell-to-cell contact for HTLV-1 transmission. Using a series of reporter systems, we show that HeLa cells cease proliferation within one or two division cycles after infection by HTLV-1 or transduction of the HTLV-1 tax gene. HTLV-1-infected HeLa cells, like their tax-transduced counterparts, expressed high levels of p21(CIP1/WAF1) and p27(KIP1), developed mitotic abnormalities, and became arrested in G(1) in senescence. In contrast, cells of a human osteosarcoma lineage (HOS) continued to divide after HTLV-1 infection or Tax expression, albeit at a reduced growth rate and with mitotic aberrations. Unique to HOS cells is the dramatic reduction of p21(CIP1/WAF1) and p27(KIP1) expression, which is in part associated with the constitutive activation of the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) pathway. The loss of p21(CIP1/WAF1) and p27(KIP1) in HOS cells apparently allows HTLV-1- and Tax-induced G(1) arrest to be bypassed. Finally, HTLV-1 infection and Tax expression also cause human SupT1 T cells to arrest in the G(1) phase of the cell cycle. These results suggest that productive HTLV-1 infection ordinarily leads to Tax-mediated G(1) arrest. However, T cells containing somatic mutations that inactivate p21(CIP1/WAF1) and p27(KIP1) may continue to proliferate after HTLV-1 infection and Tax expression. These infected cells can expand clonally, accumulate additional chromosomal abnormalities, and progress to cancer.
 ...
PMID:Human T-cell leukemia virus type 1 infection leads to arrest in the G1 phase of the cell cycle. 1859 4

Decorin is a multifunctional molecule of the extracellular matrix. Among the multitude of assigned functions the most intriguing is the ability to inhibit the growth and the metastasis of a wide range of cancer cells in vitro. Decorin was established to directly interact with EGFR and erb2, inducing protracted receptor internalization, which results in attenuation of the receptor-mediated intacellular signaling and induction of apoptosis. Studies by our group of osteosarcoma cells described the first exception to the established decorin-mediated growth suppression model. Osteosarcoma cells constitutively produced decorin and they were not sensitive to decorin-induced growth arrest. On the contrary, decorin seemed to be beneficial to osteosarcoma cells, since it was necessary for cell migration and acted as mediator, counteracting the TGFbeta2-induced cytostatic function. Importantly, decorin did not induce p21 expression whereas EGFR appeared to be overexpressed and continuously phosphorylated in our osteosarcoma model. These data provide new insight on pathways that cancer cells might employ to overcome the established decorin-induced growth suppression.
 ...
PMID:Decorin-mediated effects in cancer cell biology. 1866 52

Osteosarcoma (OS) is characterized by an unstable karyotype which typically has a heterogeneous pattern of complex chromosomal abnormalities. High-resolution array comparative genomic hybridization (CGH) in combination with interphase fluorescence in situ hybridization (FISH) analyses provides a complete description of genomic imbalances together with an evaluation of the contribution of cell-to-cell variation to copy number changes. There have been no analyses to date documenting genomic signatures consistent with chromosomal instability mechanisms in OS tumors using array CGH. In this study, we utilized high-resolution array CGH to identify and characterize recurrent signatures of genomic imbalances using ten OS tumors. Comparison between the genomic profiles identified tumor groups with low, intermediate and high levels of genomic imbalance. Bands 6p22-->p21, 8q24 and 17p12--> p11.2 were consistently involved in high copy gain or amplification events. Since these three locations have been consistently associated with OS oncogenesis, FISH probes from each cytoband were used to derive an index of cellular heterogeneity for copy number within each region. OS with the highest degree of genomic imbalance also exhibited the most extreme cell-to-cell copy number variation. Significantly, the three OS with the most imbalance and genomic copy number heterogeneity also had the poorest response to preoperative chemotherapy. This genome wide analysis is the first utilizing oligonucleotide array CGH in combination with FISH analysis to derive genomic signatures of chromosomal instability in OS tumors by studying genomic imbalance and intercellular heterogeneity. This comprehensive genomic screening approach provides important insights concerning the mechanisms responsible for generating complex genomes. The resulting phenotypic diversity can generate tumors with a propensity for an aggressive disease course. A better understanding of the underlying mechanisms leading to OS tumor development could result in the identification of prognostic markers and therapeutic targets.
 ...
PMID:Genomic signatures of chromosomal instability and osteosarcoma progression detected by high resolution array CGH and interphase FISH. 1893 80

To understand the molecular etiology of osteosarcoma, we isolated and characterized a human osteosarcoma cell line (OS1). OS1 cells have high osteogenic potential in differentiation induction media. Molecular analysis reveals OS1 cells express the pocket protein pRB and the runt-related transcription factor Runx2. Strikingly, Runx2 is expressed at higher levels in OS1 cells than in human fetal osteoblasts. Both pRB and Runx2 have growth suppressive potential in osteoblasts and are key factors controlling competency for osteoblast differentiation. The high levels of Runx2 clearly suggest osteosarcomas may form from committed osteoblasts that have bypassed growth restrictions normally imposed by Runx2. Interestingly, OS1 cells do not exhibit p53 expression and thus lack a functional p53/p21 DNA damage response pathway as has been observed for other osteosarcoma cell types. Absence of this pathway predicts genomic instability and/or vulnerability to secondary mutations that may counteract the anti-proliferative activity of Runx2 that is normally observed in osteoblasts. We conclude OS1 cells provide a valuable cell culture model to examine molecular events that are responsible for the pathologic conversion of phenotypically normal osteoblast precursors into osteosarcoma cells.
 ...
PMID:Elevated expression of Runx2 as a key parameter in the etiology of osteosarcoma. 1893 39


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>