Association of increased phosphatidylinositol 3-kinase signaling with increased invasiveness and gelatinase activity in malignant gliomas

Kubiatowski, Tomasz; Jang, Taichang; Lachyankar, Mahesh B.; Salmonsen, Rebecca; Nabi, Roya; Quesenberry, Peter J.; Litofsky, N. Scott; Ross, Alonzo H.; Recht, Larry

doi:10.3171/jns.2001.95.3.0480

Cited by 104 publications

(75 citation statements)

References 49 publications

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“…Several in vitro and in vivo experiments with glioblastoma corroborate these results. 20,21,30,31 For instance, our proliferation data are similar to results by Su et al, where dosing orthotopic mouse xenografts with LY294002 resulted in *40% inhibition of glioblastoma growth compared with controls after 5 days. The similarity in results is somewhat surprising as Su et al utilized a repeated dosing regimen compared with the static nonrenewal exposure in our experiment.…”

Section: Embryo-larval Zebrafish Xenograft Assay 325supporting

confidence: 89%

“…[34][35][36] PTEN dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)-P 3 )-mediated activation of serine/threonine kinase (AKT), thereby controlling cell proliferation, survival, migration, and invasion. 22,30,37 Inhibiting PI 3-kinase activity with LY294002 decreases glioblastoma proliferation, migration, and invasion by mitigating enhanced AKT phosphorylation.…”

Section: Embryo-larval Zebrafish Xenograft Assay 325mentioning

confidence: 99%

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Developing a Novel Embryo–Larval Zebrafish Xenograft Assay to Prioritize Human Glioblastoma Therapeutics

et al. 2016

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Glioblastoma is an aggressive brain cancer requiring improved treatments. Existing methods of drug discovery and development require years before new therapeutics become available to patients. Zebrafish xenograft models hold promise for prioritizing drug development. We have developed an embryo-larval zebrafish xenograft assay in which cancer cells are implanted in a brain microenvironment to discover and prioritize compounds that impact glioblastoma proliferation, migration, and invasion. We illustrate the utility of our assay by evaluating the well-studied, phosphatidylinositide 3-kinase inhibitor LY294002 and zinc oxide nanoparticles (ZnO NPs), which demonstrate selective cancer cytotoxicity in cell culture, but the in vivo effectiveness has not been established. Exposures of 3.125-6.25 lM LY294002 significantly decreased proliferation up to 34% with concentration-dependent trends. Exposure to 6.25 lM LY294002 significantly inhibited migration/invasion by *27% within the glioblastoma cell mass (0-80 lm) and by *32% in the next distance region (81-160 lm). Unexpectedly, ZnO enhanced glioblastoma proliferation by *19% and migration/invasion by *35% at the periphery of the cell mass (161+ lm); however, dissolution of these NPs make it difficult to discern whether this was a nano or ionic effect. These results demonstrate that we have a short, relevant, and sensitive zebrafishbased assay to aid glioblastoma therapeutic development.

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Section: Embryo-larval Zebrafish Xenograft Assay 325supporting

confidence: 89%

Section: Embryo-larval Zebrafish Xenograft Assay 325mentioning

confidence: 99%

Developing a Novel Embryo–Larval Zebrafish Xenograft Assay to Prioritize Human Glioblastoma Therapeutics

et al. 2016

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“…In vitro studies with glioma cell lines deficient in PTEN expression showed that inhibitors of PI3K (LY294002 and wortmannin), or overexpression of PTEN, reduced cell invasiveness in vitro, and this was associated with reduced activity of matrix metalloproteinases including MMP2 and MMP9 (Kubiatowski et al, 2001;Koul et al, 2001).…”

Section: Migration and Invasionmentioning

confidence: 99%

PTEN signaling in brain: neuropathology and tumorigenesis

2008

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“…18 Another study has reported that the increased invasiveness and gelatinase activity in C6 glioma cells are associated with the increase of PI3-K activity, an important downstream signaling target of EGFR, as demonstrated by LY294002, a specific PI3-K inhibitor, can inhibit the activation of Akt, expression of MMPS and the cell invasion in C6 glioma cells. 29 An U6 promoter-based RNAi gene therapy targeting PI3-K b110 subunit can inhibit U251 growth, induce apoptosis, G2/M cell cycle arrest and suppress tumor cell invasion (unpublished date). Thus, signal transduction pathways downstream of EGFR have been found to be critical in mediating important cellular functions, including survival, proliferation, migration, and invasion; inhibition of overexpressed and/or activated EGFR/PI3-K-mediated signaling pathways possess great significance in malignant glioma gene therapy.…”

Section: Biological Changes By Silenced Egfr Expressionmentioning

confidence: 99%

Suppression of EGFR expression by antisense or small interference RNA inhibits U251 glioma cell growth in vitro and in vivo

et al. 2006

Cancer Gene Ther

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Epidermal growth factor receptor (EGFR) had been reported as one of the major responsible genes for malignant progression and phenotype reversion of gliomas, and has been used as one of the most important therapeutic targets. In the present study, small interference RNA (siRNA) and antisense EGFR expression constructs, which target sequences of human EGFR catalytic domain (2400-2420) and the 3 0 -coding region, respectively, were used to examine the growth inhibition effects on U251 glioma cells. Cell growth was significantly inhibited and G2/M arrest was observed in antisense-and siRNA-treated groups. Matrigel matrix demonstrated spotted cell clustering pattern in antisense-and siRNA-transfected U251 cells, indicating poor cell growth activities. In addition, the tumor volumes in U251 subcutaneous mice model treated with antisense and siRNA were significantly smaller than those treated with control siRNA and phosphate-buffered saline. Also, glial fibrillary acidic protein expression was upregulated in antisense-and siRNA-treated groups than the control groups. Our results demonstrated that antisense-or siRNA-targeting intracellular region of EGFR can inhibit EGFR expression, exerted growth inhibition effect on U251 glioma cells in vitro and in vivo. Consequently, siRNA expression plasmid-mediated gene therapy would be a new strategy in treatment of gliomas.

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Association of increased phosphatidylinositol 3-kinase signaling with increased invasiveness and gelatinase activity in malignant gliomas

Cited by 104 publications

References 49 publications

Developing a Novel Embryo–Larval Zebrafish Xenograft Assay to Prioritize Human Glioblastoma Therapeutics

Developing a Novel Embryo–Larval Zebrafish Xenograft Assay to Prioritize Human Glioblastoma Therapeutics

PTEN signaling in brain: neuropathology and tumorigenesis

Suppression of EGFR expression by antisense or small interference RNA inhibits U251 glioma cell growth in vitro and in vivo

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