Fatty acid synthase as a novel target for meningioma therapy
Fatty acid synthase as a novel target for meningioma therapy
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DOI：
10.1093/neuonc/noq004
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发表时间：
2010-08-01
期刊：
影响因子：
15.9
通讯作者：
Mawrin, Christian
中科院分区：
文献类型：
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作者：
Haase, Daniela;Schmidl, Stefan;Mawrin, Christian
已报道在激素受体阳性肿瘤（包括前列腺癌、乳腺癌和卵巢癌）中高水平的脂肪酸合酶（FAS）表达，并且其抑制在体外和体内减少肿瘤生长。类似于其他激素受体阳性肿瘤类型，脑膜瘤是孕激素受体和雌激素受体免疫反应性脑肿瘤。为了确定FAS在人类脑膜瘤生长控制中的作用，我们首先使用包含38个脑膜瘤的组织微阵列分析了FAS表达，并显示70%的非典型WHO II级和间变性WHO III级脑膜瘤中FAS表达增加，而良性WHO I级肿瘤中FAS表达增加10%。我们接下来通过实时PCR和Western印迹证实了这一发现。第二，我们证明了FAS抑制剂浅蓝菌素（Cer）治疗显著降低了体外脑膜瘤细胞的存活率。第三，我们发现Cer处理通过调节Akt磷酸化（活化）来降低FAS表达。第四，我们证明了Cer治疗荷脑膜瘤异种移植物的小鼠导致与脑膜瘤细胞死亡增加相关的肿瘤体积显著减少。总的来说，我们的数据表明，FAS在人脑膜瘤中的表达增加代表了治疗不可切除或恶性脑膜瘤的新的治疗靶点。
High levels of fatty acid synthase (FAS) expression have been reported in hormone receptor-positive tumors, including prostate, breast, and ovarian cancers, and its inhibition reduces tumor growth in vitro and in vivo. Similar to other hormone receptor-positive tumor types, meningiomas are progesterone receptor- and estrogen receptor-immunoreactive brain tumors. To define the role of FAS in human meningioma growth control, we first analyzed the FAS expression using a tissue microarray containing 38 meningiomas and showed increased FAS expression in 70% of atypical WHO grade II and anaplastic WHO grade III meningiomas compared with 10% of benign WHO grade I tumors. We next confirmed this finding by real-time PCR and Western blotting. Second, we demonstrated that treatment with the FAS inhibitor, cerulenin (Cer), significantly decreased meningioma cell survival in vitro. Third, we showed that Cer treatment reduced FAS expression by modulating Akt phosphorylation (activation). Fourth, we demonstrated that Cer treatment of mice bearing meningioma xenografts resulted in significantly reduced tumor volumes associated with increased meningioma cell death. Collectively, our data suggest that the increased FAS expression in human meningiomas represents a novel therapeutic target for the treatment of unresectable or malignant meningioma.