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.
Highlights
Glioblastoma Multiforme (GBM) is the most common form of brain cancer in the adult and its prognosis remains poor
Quite surprisingly, the knock down of Bax appeared to promote the production of prostaglandin E2 (PGE2) in untreated U251 cells and the amount of PGE2 is maintained upon irradiation (Figure 1E), as previously observed in primary cultures of GBM [14]
Huang et al elegantly demonstrated that the proliferation signal could be generated by PGE2 produced upon activation of caspase 3, an enzyme essential for the completion of apoptosis, by radiotherapy [11]
Summary
Glioblastoma Multiforme (GBM) is the most common form of brain cancer in the adult and its prognosis remains poor. The ability of PGE2 to stimulate the proliferation of numerous types of cells has been shown both in vivo and in vitro and enzymes implicated in the synthesis of this prostanoid, such as cyclooxygenase 2 (Cox2), have been considered as a major target for anti-cancer therapies [10]. We have shown www.impactjournals.com/oncotarget that intracellular PGE2 triggers Bax, a pro-apoptotic protein, activation and as such would participate in the induction of apoptosis in both glioma and colon cancer [13,14,15]. These results suggest that PGE2 may play multiple and somewhat contradictory roles during cancer progression
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