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Increase in PGE2 biosynthesis induces a Bax dependent apoptosis correlated to patients’ survival in glioblastoma multiforme

Oncogene volume 26, pages 4999–5009 (2007)Cite this article

Abstract

Prostaglandin E2 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 PGH2 into PGE2 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 PGE2 in the culture medium failed to reproduce mPGES-1 effect on the cell viability in vitro. However, the intracellular injection of PGE2 induced a dose-dependent apoptosis in GBM cultures, which was dependent on the presence of Bax, a pro-apoptotic protein. We show that PGE2 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 PGE2 in the control of apoptosis and in its potential impact in central nervous system pathologies.

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Abbreviations

COX-2:

cyclooxygenase 2

mPGES-1:

microsomal prostaglandin E2 synthase

GBM:

Glioblastoma multiforme

BeGBM:

Bax-expressing GBM

BdGBM:

Bax-deficient GBM

PGE2:

prostaglandin E2

PGD2:

prostaglandin D2

IVT:

in vitro translated

AchE:

acetylcholine esterase

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Acknowledgements

This work was supported by a special grant from the Ligue contre le Cancer (Equipe labellisée Ligue). We thank Professor PJ Jakobsson (Karolinska Institutet, Sweden) for the gift of mPGES-1 cDNA and antibody, Dr J Grassi (CEA/Saclay, France) for the gift of AChE-coupled PGE2 and recombinant AChE, Drs P Juin and L Oliver (INSERM U601) for fruitful advices and comments. We thank also Professor JF Mosnier (Department of Anatomo-Pathology, CHU G&R Laennec, Nantes) for his support throughout this study.

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Authors and Affiliations

  1. INSERM U 601-Equipe 4, 9 Quai MONCOUSU, Cedex 01, Nantes, France

    L Lalier, P-F Cartron, F Pedelaborde, C Olivier, K Meflah, J Menanteau & F M Vallette

  2. Faculty of Medicine, University of Nantes, 9 quai MONCOUSU, Cedex 01, Nantes, France

    L Lalier, P-F Cartron, F Pedelaborde, C Olivier, K Meflah, J Menanteau & F M Vallette

  3. Department of Anatomo-Pathology, G&R Laennec Hospital, CHU, Nantes, France

    D Loussouarn

  4. Department of Neurosurgery, G&R Laennec Hospital, CHU, Nantes, France

    S A Martin

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  1. L Lalier
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Correspondence to F M Vallette.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Lalier, L., Cartron, PF., Pedelaborde, F. et al. Increase in PGE2 biosynthesis induces a Bax dependent apoptosis correlated to patients’ survival in glioblastoma multiforme. Oncogene 26, 4999–5009 (2007). https://doi.org/10.1038/sj.onc.1210303

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