Increase in PGE2 biosynthesis induces a Bax dependent apoptosis correlated to patients' survival in glioblastoma multiforme.
Prostaglandin E(2) plays multiple roles both in the physiology and the physiopathology of human brain, which are not completely understood. We have identified in a subset of human glioblastoma multiforme (GBM) tumors, the most common form of adult brain cancer, an increased expression of mPGES-1, the enzyme which catalyses the isomerization of PGH(2) into PGE(2) downstream of cyclooxygenase 2 (COX-2). The sensitivity of primary cultures of GBM to apoptosis was augmented by the overexpression of mPGES-1, whereas the knockdown of its expression by shRNA decreased the apoptotic threshold in vitro and stimulated tumor growth in vivo. Adding extracellular PGE(2) in the culture medium failed to reproduce mPGES-1 effect on the cell viability in vitro. However, the intracellular injection of PGE(2) induced a dose-dependent apoptosis in GBM cultures, which was dependent on the presence of Bax, a pro-apoptotic protein. We show that PGE(2) physically associates with Bax, triggering its apoptotic-like change in conformation and its subsequent association with mitochondria. Our results raise questions about the role of PGE(2) in the control of apoptosis and in its potential impact in central nervous system pathologies.
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INSERM U 601-Equipe 4, 9 Quai MONCOUSU, Cedex 01, Nantes, France.
Cartron
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Pedelaborde
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Olivier
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Loussouarn
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Martin
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Meflah
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Menanteau
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Vallette
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D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000096:biosynthesis* / Q000494:pharmacology; D005909:Glioblastoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D000071876:Prostaglandin-E Synthases; D015996:Survival Rate; D051028:bcl-2-Associated X Protein / Q000737:chemistry / Q000378:metabolism*
D051028:bcl-2-Associated X Protein; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone