Increase in PGE2 biosynthesis induces a Bax dependent apoptosis correlated to patients' survival in glioblastoma multiforme
Increase in PGE2 biosynthesis induces a Bax dependent apoptosis correlated to patients' survival in glioblastoma multiforme
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DOI：
10.1038/sj.onc.1210303
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发表时间：
2007-07-01
期刊：
影响因子：
8
通讯作者：
Vallette, F. M.
中科院分区：
文献类型：
--
作者：
Lalier, L.;Cartron, P-F;Vallette, F. M.
前列腺素E-2在人脑的生理学和生理学病理中发挥着多种作用，但这些作用尚不完全清楚。我们找到身份了。在人类多形性胶质母细胞瘤(GBM)肿瘤的一个亚群中，mPGES-1的表达增加，这种酶催化PGH(2)在环氧合酶2(COX-2)下游异构化为PGE(2)。MPGES-1的过表达增加了原代培养的GBM对凋亡的敏感性，而shRNA下调其表达则降低了体外的凋亡阈值，并刺激了体内肿瘤的生长。细胞外添加PGE(2)不能复制mPGES-1对细胞活力的影响。然而，细胞内注射PGE2可诱导GBM细胞发生剂量依赖性的凋亡，这依赖于促凋亡蛋白Bax的存在。我们发现PGE(2)在物理上与Bax结合，引发其在构象上的凋亡性改变，并随后与线粒体结合。我们的结果提出了关于PGE(2)在控制细胞凋亡中的作用及其在中枢神经系统病理中的潜在影响的问题。
Prostaglandin E-2 plays multiple roles both in the physiology and the physiopathology of human brain, which are not completely understood. We have identi. ed 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 PGE2 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.