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Radiation-induced PGE2 sustains human glioma cells growth and survival through EGF signaling.

Brocard E, Oizel K, Lalier L, Pecqueur C, Paris F, Vallette FM, Oliver L - Oncotarget (2015)

Bottom Line: We show that irradiated glioma cells produced and released PGE2 in important quantities independently of the induction of cell death.We demonstrate that the addition of PGE2 enhances cell survival and proliferation though its ability to trans-activate the Epithelial Growth Factor receptor (EGFR) and to activate β-catenin.Indeed, PGE2 can substitute for EGF to promote primary cultures survival and growth in vitro and the effect is likely to occur though the Prostaglandin E2 receptor EP2.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche en Cancérologie Nantes Angers UMR INSERM 892, CNRS 6299, Université de Nantes, 44007 Nantes, France.

ABSTRACT
Glioblastoma Multiforme (GBM) is the most common brain cancer in adults. Radiotherapy (RT) is the most effective post-operative treatment for the patients even though GBM is one of the most radio-resistant tumors. Dead or dying cells within the tumor are thought to promote resistance to treatment through mechanisms that are very poorly understood. We have evaluated the role of Prostaglandin E2 (PGE2), a versatile bioactive lipid, in GBM radio-resistance. We used an in vitro approach using 3D primary cultures derived from representative GBM patients. We show that irradiated glioma cells produced and released PGE2 in important quantities independently of the induction of cell death. We demonstrate that the addition of PGE2 enhances cell survival and proliferation though its ability to trans-activate the Epithelial Growth Factor receptor (EGFR) and to activate β-catenin. Indeed, PGE2 can substitute for EGF to promote primary cultures survival and growth in vitro and the effect is likely to occur though the Prostaglandin E2 receptor EP2.

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Related in: MedlinePlus

Activation of EGFR receptor monitored by ERK and β-catenin activationEGFR signaling pathway leads to the phosphorylation of ERK (pERK) and regulates β-catenin localization and stability (active β-catenin). We thus determine the percentage of pERK after incubation of primary cultures with PGE2(A) and the intracellular localization of active b-catenin, using Lithium as a positive control (B). We also analyzed the effect of PGE2 on EGFR and activeβ-catenin in the presence or in the absence of EGF (C).
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Figure 6: Activation of EGFR receptor monitored by ERK and β-catenin activationEGFR signaling pathway leads to the phosphorylation of ERK (pERK) and regulates β-catenin localization and stability (active β-catenin). We thus determine the percentage of pERK after incubation of primary cultures with PGE2(A) and the intracellular localization of active b-catenin, using Lithium as a positive control (B). We also analyzed the effect of PGE2 on EGFR and activeβ-catenin in the presence or in the absence of EGF (C).

Mentions: EGFR triggered the extracellular signal-regulated kinase (ERK)-mitogenic activated protein kinase (ERK/MAPK) signaling in many cells lines, an important component of radiation-induced hormesis [24] and glioma radio-resistance [25]. Primary cultures were treated with PGE2 and then the phosphorylation of ERK was quantified using a total phosphoERK1/2 ELISA. As shown in Figure 6A, the addition of PGE2 triggered a phosphorylation of ERK in primary cultures after 48 hours.


Radiation-induced PGE2 sustains human glioma cells growth and survival through EGF signaling.

Brocard E, Oizel K, Lalier L, Pecqueur C, Paris F, Vallette FM, Oliver L - Oncotarget (2015)

Activation of EGFR receptor monitored by ERK and β-catenin activationEGFR signaling pathway leads to the phosphorylation of ERK (pERK) and regulates β-catenin localization and stability (active β-catenin). We thus determine the percentage of pERK after incubation of primary cultures with PGE2(A) and the intracellular localization of active b-catenin, using Lithium as a positive control (B). We also analyzed the effect of PGE2 on EGFR and activeβ-catenin in the presence or in the absence of EGF (C).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466653&req=5

Figure 6: Activation of EGFR receptor monitored by ERK and β-catenin activationEGFR signaling pathway leads to the phosphorylation of ERK (pERK) and regulates β-catenin localization and stability (active β-catenin). We thus determine the percentage of pERK after incubation of primary cultures with PGE2(A) and the intracellular localization of active b-catenin, using Lithium as a positive control (B). We also analyzed the effect of PGE2 on EGFR and activeβ-catenin in the presence or in the absence of EGF (C).
Mentions: EGFR triggered the extracellular signal-regulated kinase (ERK)-mitogenic activated protein kinase (ERK/MAPK) signaling in many cells lines, an important component of radiation-induced hormesis [24] and glioma radio-resistance [25]. Primary cultures were treated with PGE2 and then the phosphorylation of ERK was quantified using a total phosphoERK1/2 ELISA. As shown in Figure 6A, the addition of PGE2 triggered a phosphorylation of ERK in primary cultures after 48 hours.

Bottom Line: We show that irradiated glioma cells produced and released PGE2 in important quantities independently of the induction of cell death.We demonstrate that the addition of PGE2 enhances cell survival and proliferation though its ability to trans-activate the Epithelial Growth Factor receptor (EGFR) and to activate β-catenin.Indeed, PGE2 can substitute for EGF to promote primary cultures survival and growth in vitro and the effect is likely to occur though the Prostaglandin E2 receptor EP2.

View Article: PubMed Central - PubMed

Affiliation: Centre de Recherche en Cancérologie Nantes Angers UMR INSERM 892, CNRS 6299, Université de Nantes, 44007 Nantes, France.

ABSTRACT
Glioblastoma Multiforme (GBM) is the most common brain cancer in adults. Radiotherapy (RT) is the most effective post-operative treatment for the patients even though GBM is one of the most radio-resistant tumors. Dead or dying cells within the tumor are thought to promote resistance to treatment through mechanisms that are very poorly understood. We have evaluated the role of Prostaglandin E2 (PGE2), a versatile bioactive lipid, in GBM radio-resistance. We used an in vitro approach using 3D primary cultures derived from representative GBM patients. We show that irradiated glioma cells produced and released PGE2 in important quantities independently of the induction of cell death. We demonstrate that the addition of PGE2 enhances cell survival and proliferation though its ability to trans-activate the Epithelial Growth Factor receptor (EGFR) and to activate β-catenin. Indeed, PGE2 can substitute for EGF to promote primary cultures survival and growth in vitro and the effect is likely to occur though the Prostaglandin E2 receptor EP2.

Show MeSH
Related in: MedlinePlus