UMLS:C0029463 - FACTA Search

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

Epidermal growth factor (EGF) induces a rapid increase in the phosphorylation of extracellular signal-regulated kinases (ERKs) in the human osteosarcoma osteoblastic cell line G292 and in primary cultures of rat osteoblastic cells. This phosphorylation is transient and time-dependent. Maximal stimulation is attained within 1 min in G292 and within 5 min in rat osteoblastic cells. Enzymatic activity in G292 cells is also induced rapidly after EGF stimulation. Western blot analysis revealed that enhancement of the phosphorylation of ERKs in the EGF-stimulated cells is not due to an increase in ERK protein, since EGF-treatment does not lead to an increase in the absolute amount of ERKs present even after 2 days of stimulation. The pattern of expression of the ERKs observed in the two cell types differs in the apparent molecular weights observed. The most slowly migrating immunoreactive protein (approximately 45 kDa) in normal rat osteoblastic cells is ERK1, identified by an ERK1-selective antiserum. The same antiserum reacts only weakly with one of the ERK proteins (44 kDa) blotted from the human osteosarcoma cell line G292. Phorbol 12-myristate 13-acetate (PMA) is also capable of inducing ERK phosphorylation, albeit to a lasser degree. The combination of PMA and EGF does not produce a greater response than EGF alone. The role of protein kinase C (PKC) in the EGF-stimulated ERK signaling pathway was further examined by inhibition of PKC with the staurosporine analog, CGP41251, and by down-regulation of PKC via chronic treatment with PMA. Chronic PMA treatment results in a partial inhibition of the EGF-mediated phosphorylation. CGP41251 completely abolishes the increased ERK activity produced by PMA, but the effect of EGF in this regard is potentiated. We conclude that PKC and EGF act through parallel pathways to stimulate ERK phosphorylation and activity. The inhibitor studies, in addition, indicate that activation of PKC may moderate the actions of the EGF pathway via a tonic inhibitory feedback.
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PMID:EGF-mediated phosphorylation of extracellular signal-regulated kinases in osteoblastic cells. 786 Jun 43

Fluoride, at micromolar concentrations, stimulates bone cell proliferation in vitro. In this study, we sought to test whether fluoride at mitogenic doses increases the tyrosyl phosphorylation level and specific activity of a mitogen-activated protein kinase (MAPK) in human TE85 osteosarcoma cells. Analysis by immunoprecipitation with antiphosphotyrosine antibody followed by Western analysis using an anti-pan extracellular signal-regulated kinase antibody revealed that fluoride at the optimal mitogenic dose (i.e. 100 mumol/L) induced a time-dependent increase in the steady state tyrosyl phosphorylation level of p44mapk, but not p42mapk, with the maximal increase (4- to 13-fold) after 1-3 h fluoride treatment. The effect was sustained in that a 9-fold increase was seen after 12 h of the fluoride treatment. The sustained nature of the effect is consistent with an inhibition of dephosphorylation rather than a direct stimulation of phosphorylation. The fluoride effect on the tyrosyl phosphorylation level of p44mapk was dose dependent, with the optimal dose being 100 mumol/L fluoride. The mitogenic dose of fluoride also increased the specific activity and the in-gel kinase activity of p44mapk, but not that of p42mapk, in a time-dependent manner similar to the effect on the p44mapk tyrosyl phosphorylation level. Fluoride at the same micromolar doses did not increase cell proliferation, tyrosyl phosphorylation, or specific activity of any MAPK in human skin foreskin fibroblasts, which are fluoride-nonresponsive cells. Consistent with the interpretation that the effect of fluoride on the steady state tyrosyl phosphorylation level of p44mapk is a consequence of an inhibition of a phosphotyrosyl phosphatase (PTP), mitogenic doses of orthovanadate, a bone cell mitogen and a PTP inhibitor, also increased the steady state tyrosyl phosphorylation level of p44mapk, but not p42mapk, in a time-dependent sustained manner similar to that observed with fluoride. Together, these findings support the concept that inhibition of a PTP activity in bone cells could lead to an activation of MAPK activity.
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PMID:Fluoride at mitogenic doses induces a sustained activation of p44mapk, but not p42mapk, in human TE85 osteosarcoma cells. 910 May 84

The activation of extracellular signal-regulated kinases 1 and 2 by insulin-like growth factor I in human osteosarcoma MG-63 cells was examined by Mono Q ion exchange chromatography of cell extracts and measurement of myelin basic protein kinase activity, and by immunoblotting of cell extracts with a phospho-specific extracellular signal-regulated kinase antibody. Extracellular signal-regulated kinase 1 appeared to be activated in resting cells and addition of insulin-like growth factor I resulted in the activation primarily of extracellular signal-regulated kinase 2. Extracellular signal-regulated kinase 2 was found in the nucleus after addition of insulin-like growth factor I.
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PMID:Activation of extracellular signal-regulated kinases 1 and 2 by insulin-like growth factor I in human osteosarcoma MG-63 cells. 1022 83

When osteoblasts are cultured on surfaces of increasing microroughness, they exhibit decreases in proliferation, increases in differentiation and local factor production, and enhanced response to 1alpha,25(OH)(2)D(3). The cells interact with surfaces through integrins, which signal by the same pathways used by 1alpha,25(OH)(2)D(3), including protein kinase C via phospholipase C and protein kinase A via phospholipase A(2). This provides opportunities for crosstalk that may contribute to the synergistic effects of surface roughness and the vitamin D metabolite. Because these pathways converge at mitogen-activated protein kinase (MAPK), we tested the hypothesis that the extracellular signal-regulated kinase (ERK1/2) subclass of MAPKs mediates the effects of surface roughness and 1alpha,25(OH)(2)D(3). MG63 osteoblast-like osteosarcoma cells were cultured on commercially pure Ti disks with various surface roughnesses: pretreatment (PT; 0.6 microm average roughness [Ra]), coarse grit-blasted and acid-etched (SLA; 4 microm RA), and titanium plasma-sprayed (TPS; 5.2-microm R(a)). At confluence, cells were treated for 24 h with control media or media containing 10(-7) M 1alpha,25(OH)(2)D(3). One-half of the cultures received 1 microm or 10 microm PD98059, a specific inhibitor of the ERK family of MAPKs. PD98059 alone did not affect proliferation, osteocalcin production, or production of transforming growth factor-beta1 or nitric oxide, regardless of the surface roughness. Alkaline phosphatase was reduced by the inhibition of the ERK family kinases on all surfaces to a comparable extent. However, when PD98059 was added to the cultures with 1alpha,25(OH)(2)D(3), the effects of the seco-steroid were blocked, including the synergistic increases seen in MG63 cells cultured on SLA or TPS. These results indicate that ERK1/2 MAPK is required for the maintenance of alkaline phosphatase at control levels and that the effects of 1alpha,25(OH)(2)D(3) are mediated by ERK1/2. However, the effects of surface roughness are not due to the ERK family of MAPKs. This suggests that alternative pathways may be used, including those mediated by other MAPK subclasses.
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PMID:Osteoblast response to titanium surface roughness and 1alpha,25-(OH)(2)D(3) is mediated through the mitogen-activated protein kinase (MAPK) pathway. 1137 60

Cellular stress activates multiple mitogen-activated protein kinase (MAPK) cascades and immediate-early gene (IEG) transcription. To address how these events are linked, we investigated the endogenous signaling/transcription factor network driving IEG activation by arsenite and anisomycin in the human osteosarcoma cell line HOS/TE-85. Induction of IEG transcription by both stresses corresponded temporally with the phosphorylation of the regulatory factors Elk-1 and cAMP response element-binding protein (CREB), along with activation of the extracellular signal-regulated kinase (ERK), stress-activated protein kinase (SAPK) and p38 MAPK cascades. To assess the role of the different cascades, they were selectively inhibited with PD98059, SP600125 and SB203580, respectively. This implicated all three cascades in Elk-1 phosphorylation after arsenite treatment, whereas ERK and SAPK inhibition diminished this, and IEG mRNA levels, downstream of anisomycin. SB blocked phosphorylation of both serum response factor (SRF) and CREB, and strongly reduced IEG activation by both stresses. Combining PD with SB further reduced arsenite induction of IEG transcription. Thus, all three MAPK cascades mediate anisomycin- and arsenite-induced signaling to IEG promoters in HOS cells through the differential targeting of Elk-1, SRF and CREB.
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PMID:Immediate-early gene induction by the stresses anisomycin and arsenite in human osteosarcoma cells involves MAPK cascade signaling to Elk-1, CREB and SRF. 1266 Aug 19

Polycyclic aromatic hydrocarbons (PAHs) have been known as a kind of xenoestrogen. Benzo[a]pyrene, a PAH present in tobacco smoke and tar, has been implicated in the induction of cell proliferation as well as tumors including osteosarcoma. Nevertheless, the literature about the action of benzo[a]pyrene on the bone system is rare. It has been identified that osteoblasts owned the estrogen receptors and estrogen could modulate the osteoblast proliferation. In this study, we found that benzo[a]pyrene was capable of increasing the cell proliferation in cultured rat osteoblasts, human osteosarcoma cell line (MG-63), and estrogen sensitive human cell line (MCF-7) but not in the human estrogen receptor negative cell line (MDA-MB-231). This benzo[a]pyrene-induced osteoblast proliferation could be inhibited by the estrogen receptor antagonist ICI182780 and tamoxifen, PD98059 [extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) inhibitor], and LY294002 [phosphatidylinositol 3-kinase (PI3K) inhibitor] but not alpha-naphthoflavone (aryl hydrocarbon receptor antagonist) and SB203580 (p38 MAPK inhibitor). Western blot analysis showed that benzo[a]pyrene could induce the phosphorylation of ERK1/2 and Akt (PI3K downstream effector) in osteoblasts. The proliferating cell nuclear antigen protein levels in nuclear fraction of osteoblasts were also increased by benzo[a]pyrene. Moreover, cyclooxygenase-2 (COX-2), but not COX-1, expression could be induced in osteoblasts under benzo[a]pyrene treatment. Its upregulation was associated with the induction of prostaglandin E(2) (PGE(2)). COX-2 inhibitors NS398 and aspirin are capable of inhibiting the benzo[a]pyrene-induced osteoblast proliferation. These results indicate that benzo[a]pyrene may modulate the osteoblast proliferation through activation of COX-2 protein.
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PMID:Benzo[a]pyrene regulates osteoblast proliferation through an estrogen receptor-related cyclooxygenase-2 pathway. 1514 25

We investigated the effects of bradykinin (BK) on the production of interleukin (IL)-6 and prostaglandin PGE(2), whose molecules are capable of stimulating the development of osteoclasts from their hematopoietic precursors as well as the signal transduction systems involved, in human osteoblasts (SaM-1 cells). BK receptors B1 (B1R) and B2 (B2R) were expressed in SaM-1 and osteosarcoma (SaOS-2, HOS, and MG-63) cells. Treatment of SaM-1 cells with BK increased the synthesis of both IL-6 and PGE(2) and the increase in both was blocked by HOE140 (B2R antagonist), but not by Des-Arg(9)-[Leu(8)]-BK (B1R antagonist). U-73122, a phospholipase C (PLC) inhibitor, suppressed BK-induced IL-6 and PGE(2) synthesis in SaM-1 cells. In addition, BK caused an increase in the intracellular Ca(2+) concentration ([Ca(2+)]i), which was inhibited by pretreatment with HOE140 or 2-aminoethoxydiphenyl borate (2-APB), an inositol 1,4,5-trisphosphate (IP(3)) receptor (IP(3)R) blocker. Furthermore, both SB203580 (an inhibitor of p38 mitogen-activated protein kinase [MAPK]) and PD98059 (an inhibitor of MEK, upstream of ERK) attenuated the BK-induced IL-6 and PGE(2) synthesis. BK treatment resulted in the phosphorylation of p38 MAPK and extracellular signal-regulated kinase (ERK)1/2, and 2-APB could suppress BK-induced phosphorylation of ERK1/2. These findings suggest that BK increased both IL-6 and PGE(2) synthesis in osteoblastic cells via B2R and that PLC, IP(3)-induced [Ca(2+)]i, MEK, and MAPKs were involved in the signal transduction in these cells.
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PMID:Activation of osteoblastic functions by a mediator of pain, bradykinin. 1534 32

The chemopreventive activity of resveratrol (RSVL) has been demonstrated in several types of cancer. However, its effects and the underling mechanisms remain poorly understood. In this study, we investigated the involvement of the mitogen activated protein kinase (MAPK)/p53 signal transduction mechanism in RSVL-induced growth inhibition using a human osteosarcoma cell line. We demonstrate that RSVL reduces cell viability and growth of SJSA1 osteosarcoma cells. Morphological profiles and 4,6-diamidino-2-phenylindole nuclear staining of RSVL-treated cells indicated marked nuclear fragmentation. Cleavage of the (116-kDa) poly(ADP-ribose) polymerase protein into an 89-kDa fragment (a proapoptotic marker system) was substantially augmented by RSVL treatment. RSVL-dependent growth impairment was preceded by enhanced phosphorylation of extracellular signal-regulated kinase (ERK)1/2 (at Thr202/Tyr204). Likewise, RSVL increased the phosphorylation of p53 tumor suppressor protein (at Ser15). The effects of RSVL on ERKs and on p53 phosphorylation were abrogated by either the MAPK inhibitor PD98059 or the p53 inhibitor pifithrine-alpha. The present study indicates that RSVL antiproliferative effects on osteosarcoma cells are mediated by the activation of the ERKs/p53 signaling pathway and therefore identifies new targets for strategies to treat and/or prevent osteosarcoma.
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PMID:Potent antiproliferative effects of resveratrol on human osteosarcoma SJSA1 cells: Novel cellular mechanisms involving the ERKs/p53 cascade. 1681 13

The circadian timing system and the cell division cycle are frequently deregulated in cancer. The therapeutic relevance of the reciprocal interactions between both biological rhythms was investigated using Seliciclib, a cyclin-dependent kinase (CDK) inhibitor (CDKI). Mice bearing Glasgow osteosarcoma received Seliciclib (300 mg/kg/d orally) or vehicle for 5 days at Zeitgeber time (ZT) 3, 11, or 19. On day 6, tumor mRNA 24-hour expression patterns were determined for clock genes (Per2, Rev-erbalpha, and Bmal1) and clock-controlled cell cycle genes (c-Myc, Wee1, cyclin B1, and CDK1) with quantitative reverse transcription-PCR. Affinity chromatography on immobilized Seliciclib identified CDK1/CDK2 and extracellular signal-regulated kinase (ERK) 1/ERK2, CDK7/CDK9, and casein kinase CK1epsilon as Seliciclib targets, which respectively regulate cell cycle, transcription, and circadian clock in Glasgow osteosarcoma. Seliciclib reduced tumor growth by 55% following dosing at ZT3 or ZT11 and by 35% at ZT19 compared with controls (P < 0.001). Tolerability was also best at ZT3. Mean transcriptional activity of Rev-erbalpha, Per2, and Bmal1 was arrhythmic in the tumors of untreated mice. Seliciclib induced rhythmic clock gene expression patterns with physiologic phase relations only after ZT3 dosing. c-Myc and Wee1 mRNAs displayed synchronous circadian rhythms in the tumors of control mice receiving vehicle only but not in those of mice given the drug. Seliciclib further enhanced Wee1 expression irrespective of dosing time, an effect that reinforced G(2)-M gating. Seliciclib also inhibited CK1epsilon, which determines circadian period length. The coordination of clock gene expression patterns in tumor cells was associated with best antitumor activity of Seliciclib. The circadian clock and its upstream regulators represent relevant targets for CDKIs.
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PMID:Improved tumor control through circadian clock induction by Seliciclib, a cyclin-dependent kinase inhibitor. 1710 8

Intermittent administration of the N-terminal fragment of parathyroid hormone (PTH) and PTH-related protein (PTHrP) induces bone anabolic effects. However, the effects of the C-terminal domain of PTHrP on bone turnover remain controversial. We examined the putative mechanisms whereby this PTHrP domain can affect osteoblastic differentiation, using human osteosarcoma MG-63 cells and osteoblastic cells from human trabecular bone. Intermittent exposure to PTHrP (107-139), within 10-100 nM, for only <or=24 hours during cell growth stimulated alkaline phosphatase (ALP) and Runt homology domain protein (Runx2) activities as well as osteocalcin (OC) and osteoprotegerin (OPG) expression but inhibited receptor activator of nuclear factor kappaB (NF-kappaB) ligand. Continuous exposure to this PTHrP peptide reversed these effects. The stimulatory effects of transient treatment with PTHrP (107-139) on OC mRNA and/or OPG protein expression were unaffected by a neutralizing anti-insulin-like growth factor I antibody or [Asn(10), Leu(11), d-Trp(12)]PTHrP (7-34) in these cells. On the other hand, the former antibody and the latter PTHrP antagonist abrogated the PTHrP (1-36)-induced increase in these osteoblastic products. Transient exposure to PTHrP (107-139), in contrast to PTHrP (1-36), stimulated vascular endothelial growth factor receptor 2 (VEGFR2) mRNA levels in these cells. Moreover, induction of ALP activity as well as OC and OPG expression by PTHrP (107-139) was blunted by SU5614, a permeable tyrosine kinase inhibitor of VEGFR2. Protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) inhibitors abolished the PTHrP (107-139)-stimulated VEGFR2 and OPG mRNA levels in these cells. These results indicate that intermittent exposure to PTHrP (107-139) exerts potential anabolic effects through the PKC/ERK pathway and, subsequently, VEGFR2 upregulation in vitro in human osteoblastic cells.
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PMID:Transient exposure to PTHrP (107-139) exerts anabolic effects through vascular endothelial growth factor receptor 2 in human osteoblastic cells in vitro. 1712 Jan 84

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