Tumor necrosis factor-like weak inducer of apoptosis stimulation of glioma cell survival is dependent on Akt2 function.
Tumor necrosis factor-like weak inducer of apoptosis stimulation of glioma cell survival is dependent on Akt2 function.
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DOI：
10.1158/1541-7786.mcr-09-0194
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发表时间：
2009-11
期刊：
影响因子：
--
通讯作者：
Tran NL
中科院分区：
文献类型：
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作者：
Fortin SP;Ennis MJ;Savitch BA;Carpentieri D;McDonough WS;Winkles JA;Loftus JC;Kingsley C;Hostetter G;Tran NL
恶性胶质瘤是最常见的原发性脑肿瘤。尽管深入的临床研究和外科和放射治疗的重大技术进步，对恶性胶质瘤患者的临床结果的影响是令人失望的。我们之前已经证明，作为TNF超家族成员的TWEAK可以通过结合Fn14受体、激活NF-κB通路和上调BCL-XL基因表达来刺激胶质瘤细胞的存活。在这里，我们发现TWEAK处理胶质瘤细胞导致Akt和BAD磷酸化。TWEAK刺激会导致Akt1和Akt2的磷酸化。然而，sirna介导的Akt1或Akt2缺失表明BAD丝氨酸136磷酸化特异性依赖于Akt2功能。通过siRNA去除Akt2的表达也会破坏twist刺激的胶质瘤细胞的存活，而siRNA介导的Akt1表达去除对胶质瘤细胞存活没有影响。令人惊讶的是，尽管在胶质瘤细胞中sirna介导的BAD缺失消除了细胞毒性和化疗诱导的细胞凋亡，但TWEAK仍然显示出强大的保护作用，这表明BAD丝氨酸136磷酸化在TWEAK- akt2诱导的胶质瘤细胞存活中起着次要作用。我们也在这里报道AKT2基因表达水平随着胶质瘤级别的增加而增加，并与患者生存呈负相关。此外，免疫组织化学分析显示，在GBM标本中，Akt2的表达与Fn14的表达呈正相关。我们假设，微调fn14信号轴通过激活Akt2丝氨酸/苏氨酸蛋白激酶，在一定程度上增强胶质母细胞瘤细胞的存活。
Malignant gliomas are the most common primary brain tumors. Despite intensive clinical investigation and significant technical advances in surgical and radiation treatment, the impact on clinical outcome for patients with malignant gliomas is disappointing. We have previously shown that TWEAK, a member of the TNF superfamily, can stimulate glioma cell survival via binding to the Fn14 receptor, activation of the NF-κB pathway, and up-regulation of BCL-XL gene expression. Here, we show that TWEAK treatment of glioma cells leads to phosphorylation of Akt and BAD. TWEAK stimulation results in the phosphorylation of both Akt1 and Akt2. However, siRNA-mediated depletion of either Akt1 or Akt2 showed that BAD serine 136 phosphorylation is dependent specifically on Akt2 function. Depletion of Akt2 expression by siRNA also abrogates TWEAK-stimulated glioma cell survival, whereas no effect on glioma cell survival was observed after siRNA-mediated depletion of Akt1 expression. Surprisingly, although siRNA-mediated depletion of BAD in glioma cells abrogates cytotoxic- and chemotherapy-induced apoptosis, TWEAK still display a strong protective effect, suggesting that BAD serine 136 phosphorylation plays a minor role in TWEAK-Akt2 induced glioma cells survival. We also report here that AKT2 gene expression levels increased with glioma grade and inversely correlate with patient survival. Additionally, immunohistochemical analysis showed that Akt2 expression positively correlates with Fn14 expression in GBM specimens. We hypothesize that the TWEAK-Fn14 signaling axis functions, in part, to enhance glioblastoma cell survival by activation of the Akt2 serine/threonine protein kinase.