Evidence for phosphatidylinositol 3-kinase—Akt—p70S6K pathway activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells

2002 ◽  
Vol 97 (3) ◽  
pp. 668-675 ◽  
Author(s):  
Mahlon D. Johnson ◽  
Evelyn Okediji ◽  
Ann Woodard ◽  
Steven A. Toms ◽  
George S. Allen
Keyword(s):  
Growth Factor ◽  
Western Blot ◽  
Blot Analysis ◽  
Platelet Derived Growth Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Content Type ◽  
Phosphorylated Akt ◽  
Fine Print ◽  
Stimulation Of ◽  
Mitogenic Signals

Object. The intracellular events transducing mitogenic signals from platelet-derived growth factor—β (PDGFβ) receptor tyrosine kinases are not precisely known. In this study the authors evaluated whether the phosphatidylinositol 3-kinase (PI3-K)—Akt—p70S6K pathway is expressed in meningiomas, regulates their growth, and transduces mitogenic signals of PDGF-BB. Methods. Nine meningioma tumors obtained in humans were evaluated using Western blot analysis for phosphorylated (activated) Akt and phosphorylated p70S6K. Cells cultured from seven of these meningiomas were also screened using Western blot analysis for Akt and for phosphorylated Akt and p70S6K. The authors also evaluated whether PDGF-BB stimulation of meningioma cells was associated with the phosphorylation of Akt and p70S6K known to activate these kinases. In addition, the effects of wortmannin, an inhibitor of PI3-K, on proliferation and activation of Akt and p70S6K in meningioma cells stimulated with PDGF-BB were evaluated. Western blots of lysates from meningiomas demonstrated phosphorylated Akt and p70S6K. Treatment with PDGF-BB stimulated phosphorylation of Akt and p70S6K in each meningioma cell culture. Wortmannin (500 and 1000 nM) significantly decreased PDGF-BB stimulation of meningioma cells (p < 0.001) while it reduced Akt and p70S6K phosphorylation but not mitogen-activated protein kinase/extracellular signal—regulated kinase (MAPK/ERK) phosphorylation. Conclusions. These findings indicate that Akt and p70S6K are constitutively expressed and activated in meningioma cells and that the PI3-K—Akt—p70S6K pathway may participate in transduction of mitogenic signals in meningiomas independent of the Raf-1—MEK-1—MAPK/ERK cascade.

Evidence for mitogen-associated protein kinase activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells

2001 ◽  
Vol 94 (2) ◽  
pp. 293-300 ◽  
Author(s):  
Mahlon D. Johnson ◽  
Ann Woodard ◽  
Paul Kim ◽  
Maria Frexes-Steed
Keyword(s):  
Growth Factor ◽  
Thymidine Incorporation ◽  
Platelet Derived Growth Factor ◽  
Mapk Phosphorylation ◽  
Content Type ◽  
Human Meningiomas ◽  
Β Receptor ◽  
Fine Print ◽  
Stimulation Of ◽  
Mitogenic Signals

Object. Coexpression of platelet-derived growth factor (PDGF)—BB and activated PDGF-β receptor in meningioma cells indicates that this cytokine may act as an autocrine or paracrine stimulant of meningioma growth. The intracellular events transducing signals from PDGF-β receptor tyrosine kinases are unknown. In this study the authors evaluated whether or not mitogen-activated protein kinases (MAPKs) are expressed in meningiomas, regulate their growth, and transduce mitogenic signals of PDGF-BB. Methods. Ten human meningioma tumors as well as cells cultured from two normal leptomeninges and 10 additional human meningiomas were evaluated using Western blot analysis to determine the presence of MAPK and phosphorylated (activated) MAPK. The effects of PD098059, a selective inhibitor of MAPK phosphorylation/activation, on proliferation of meningioma cells stimulated with 10% fetal bovine serum was also evaluated. Last, the authors evaluated whether PDGF-BB stimulation of meningioma cells was associated with activation of MAPK. Western blots of lysates from meningiomas and from cultured leptomeningeal and meningioma cells demonstrated MAPK and phosphorylated MAPK. Treatment with PD098059 produced a 52 to 84% (x = 69.8) loss in [3H]thymidine incorporation, which was associated with a partial or complete loss of phosphorylated MAPK after 3 days of treatment. The PDGF-BB produced a significant increase in [3H]thymidine incorporation and phosphorylation of MAPK at 1 and 3 days. Coadministration of PD098059 completely blocked PDGF-BB's stimulation of [3H]thymidine incorporation and cell proliferation concomitant with reduced MAPK phosphorylation. Conclusions. The findings indicate that MAPK is constitutively expressed in leptomeningeal and meningioma cells and transduces mitogenic signals of PDGF, contributing to the growth of human meningiomas.

Antiproliferative effect of trapidil, a platelet-derived growth factor antagonist, on a glioma cell line in vitro

1990 ◽  
Vol 73 (3) ◽  
pp. 436-440 ◽  
Author(s):  
Jun-ichi Kuratsu ◽  
Yukitaka Ushio
Keyword(s):  
Growth Factor ◽  
Cell Lines ◽  
Glioma Cell ◽  
Glioma Cells ◽  
Inhibitory Effect ◽  
Platelet Derived Growth Factor ◽  
Content Type ◽  
Glioma Cell Lines ◽  
Fine Print

✓ Platelet-derived growth factor (PDGF) is produced by glioma cells. However, there is heterogeneity among glioma cell lines in the production of PDGF. It has been demonstrated that U251MG cells produce a PDGF-like molecule while U105MG cells do not. Trapidil, a specific antagonist of PDGF, competes for receptor binding with PDGF. Therefore, the inhibitory effect of trapidil on the proliferation of glioma cells was investigated in vitro using two glioma cell lines. At 100 µg/ml, trapidil significantly inhibited the proliferation of U251MG cells (which produce the PDGF-like molecule). At the same trapidil concentration, the proliferation of U105MG cells (which do not produce the PDGF-like molecule) was not inhibited. The inhibitory effect of trapidil was remarkable on Days 3 and 4 of culture. After 4 days of incubation, the proliferation of U251MG cells was 46% of the control preparation. Trapidil enhanced the antitumor effect of 3-((4-amino-2-methyl-5-pyrimidinyl)ethyl)-1-(2-chloroethyl)-1-nitro-sourea (ACNU) against U251MG cells. The enhancing effect was highest on Days 4 and 6 of culture. After 6 days of incubation in the presence of 100 µg/ml trapidil and 1 µg/ml ACNU, the proliferation of U251MG cells was 18% of the control preparation. These findings suggest that trapidil interrupts the autocrine loop at the PDGF and PDGF-receptor level and that combination therapy with trapidil and ACNU may be useful in the treatment of glioma.

Combined inhibition of vascular endothelial growth factor and platelet-derived growth factor signaling: effects on the angiogenesis, microcirculation, and growth of orthotopic malignant gliomas

2005 ◽  
Vol 102 (2) ◽  
pp. 363-370 ◽  
Author(s):  
Mohammad Reza Farhadi ◽  
Hans Holger Capelle ◽  
Ralf Erber ◽  
Axel Ullrich ◽  
Peter Vajkoczy
Keyword(s):  
Growth Factor ◽  
Tumor Growth ◽  
Malignant Gliomas ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Vascular Endothelial ◽  
Tumor Implantation ◽  
Content Type ◽  
Endothelial Growth Factor ◽  
Fine Print

Object. The goal of this study was to determine the effects of SU6668, a polyvalent receptor tyrosine kinase inhibitor against vascular endothelial growth factor receptor—2, platelet-derived growth factor receptor—β, and fibroblast growth factor—1 on tumor growth, angiogenesis, and microcirculation in an orthotopic malignant glioma model. Methods. Fluorescently labeled C6 malignant glioma cells were implanted into a long-term cranial window, which had been prepared in nude mice. The animals were treated with intraperitoneal injections of SU6668 (75 mg/kg/day) immediately (five animals) or 7 days (five animals) following tumor implantation. Control mice received intraperitoneal injections of vehicle (50 µl dimethylsulfoxide) immediately (five animals) or 7 days (four animals) after tumor implantation. Tumor growth, angiogenesis, and microcirculation were assessed by performing intravital fluorescence videomicroscopy over a 14-day observation period. To assess the effects of SU6668 on overall survival, C6 glioma cells were implanted stereotactically into the brains of 24 additional animals and treatment was initiated on Day 7. In both the immediate and delayed experimental setting, SU6668 treatment resulted in a significant reduction of total and functional tumor vessel densities (both p < 0.05), reflecting a suppression of angiogenesis and impairment of tumor perfusion. As a consequence, tumor growth was significantly inhibited (p < 0.05). Histological analysis demonstrated reduced tumor growth and less mass effect on the adjacent brain of treated animals. The survival experiments confirmed the importance of our results in that survival was significantly prolonged following SU6668 therapy (p < 0.05). Conclusions. Targeting of multiple angiogenic signaling pathways by polyvalent tyrosine kinase inhibitors represents a promising strategy to interfere with the vascularization, microcirculation, and growth of angiogenesis-dependent tumors. This also applies to malignant gliomas, despite the uniqueness of the cerebral microenvironment and the singular pathobiology of this tumor entity.

scholarly journals TC10α Is Required for Insulin-Stimulated Glucose Uptake in Adipocytes

Endocrinology ◽  
2007 ◽  
Vol 148 (1) ◽  
pp. 27-33 ◽  
Author(s):  
Louise Chang ◽  
Shian-Huey Chiang ◽  
Alan R. Saltiel
Keyword(s):  
Plasma Membrane ◽  
Growth Factor ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Platelet Derived Growth Factor ◽  
Phosphatidylinositol 3 Kinase ◽  
Independent Manner ◽  
Rho Family ◽  
Glucose Transporter Glut4 ◽  
Stimulation Of

Previous studies have suggested that activation of the Rho family member GTPase TC10 is necessary but not sufficient for the stimulation of glucose transport by insulin. We show here that endogenous TC10α is rapidly activated in response to insulin in 3T3L1 adipocytes in a phosphatidylinositol 3-kinase-independent manner, whereas platelet-derived growth factor was without effect. Knockdown of TC10α but not TC10β by RNA interference inhibited insulin-stimulated glucose uptake as well as the translocation of the insulin-sensitive glucose transporter GLUT4 from intracellular sites to the plasma membrane. In contrast, loss of TC10α had no effect on the stimulation of Akt by insulin. Additionally, knockdown of TC10α inhibited insulin-stimulated translocation of its effector CIP4. These data indicate that TC10α is specifically required for insulin-stimulated glucose uptake in adipocytes.

Heparin reduces proliferative angiopathy following subarachnoid hemorrhage in cats

1985 ◽  
Vol 62 (4) ◽  
pp. 570-575 ◽  
Author(s):  
John P. Kapp ◽  
Ben R. Clower ◽  
Frederick M. Azar ◽  
Nobuyoshi Yabuno ◽  
Robert R. Smith
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Growth Factor ◽  
Middle Cerebral Artery ◽  
Cerebral Artery ◽  
Cerebral Arteries ◽  
Platelet Derived Growth Factor ◽  
Platelet Factor ◽  
Content Type ◽  
The Right ◽  
Fine Print

✓ Subarachnoid hemorrhage (SAH) was produced in cats by transorbital rupture of the right middle cerebral artery (MCA). In untreated cats, widespread proliferative angiopathy occurred in both MCA's by 16 days after SAH. In cats that received systemic heparin, the pathological events following SAH were clearly reduced in the ruptured artery, and were not present in the contralateral left MCA. Platelets are known to adhere to the subintimal surface of cerebral arteries after SAH. The authors suggest that platelet-derived growth factor released from the intimal platelet carpet following SAH may be the stimulus for the development of proliferative angiopathy, and that this platelet factor is inhibited by heparin.

Platelet-derived growth factor expression and stimulation in human meningiomas

1994 ◽  
Vol 81 (3) ◽  
pp. 388-393 ◽  
Author(s):  
Peter McL. Black ◽  
Rona Carroll ◽  
Danuta Glowacka ◽  
Kathleen Riley ◽  
Kathleen Dashner
Keyword(s):  
Growth Factor ◽  
Messenger Rna ◽  
Thymidine Incorporation ◽  
Linear Regression Analysis ◽  
Platelet Derived Growth Factor ◽  
Content Type ◽  
Human Meningiomas ◽  
Meningioma Cell ◽  
Β Receptor ◽  
Fine Print

✓ The platelet-derived growth factor (PDGF) family consists of subunits A and B and receptors α and β. This paper evaluates the potential role of the homodimer PDGF-BB as a growth factor in meningiomas. It analyzes the expression of messenger RNA in members of the PDGF family in these tumors, measures the growth response of meningiomas to exogenous PDGF-BB in culture, and examines the induction of the c-fos proto-oncogene by PDGF-BB. Northern blot analysis was carried out on tissue from 20 meningiomas to measure the expression of PDGF-A, PDGF-B, PDGF-α receptor (PDGF-α-R) and PDGF-β receptor (PDGF-β-R). All tumors expressed PDGF-A and PDGF-B subunits. Nineteen of the 20 tumors expressed PDGF-β-R and none expressed PDGF-α-R as measured by this technique. Because the β receptor is selectively sensitive to stimulation by the PDGF-B subunit, these data suggest that meningiomas might be susceptible to stimulation by PDGF-BB. To test this hypothesis, the effect of exogenous PDGF-BB on meningioma growth was evaluated by incubating cells from 10 human meningiomas. Tritiated thymidine incorporation was used to evaluate stimulation of growth over a 48-hour period using PDGF-BB concentrations of 1, 3, or 6 ng/ml. Linear regression analysis and multiple-factor analysis of variance were used to measure PDGF-BB effects. Three of the 10 tumor specimens responded significantly to PDGF-BB, with a three- to sixfold increase in thymidine incorporation over 72 hours of exposure, and there was a significant overall growth-stimulating effect of PDGF-BB in the 10 tumor specimens tested. In the last set of experiments, the functionality of the PDGF-β-R was determined by examining the induction of the proto-oncogene c-fos by PDGF-BB in meningioma cell cultures. A significant increase in c-fos protein was observed 3 hours after PDGF-BB addition. These findings demonstrate that PDGF-A, PDGF-B, and PDGF-β-R are expressed in meningiomas and suggest that the β receptor is functional: when it is activated, c-fos levels are increased, and an increase in meningioma cell division is observed after the addition of PDGF-BB. These studies support the hypothesis that PDGF acts as a growth factor in meningiomas.

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