Overexpression of fatty acid synthase in human gliomas correlates with the WHO tumor grade and inhibition with Orlistat reduces cell viability and triggers apoptosis
Overexpression of fatty acid synthase in human gliomas correlates with the WHO tumor grade and inhibition with Orlistat reduces cell viability and triggers apoptosis
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DOI：
10.1007/s11060-014-1452-z
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发表时间：
2014-06-01
影响因子：
3.9
通讯作者：
Ewald, Christian
中科院分区：
文献类型：
--
作者：
Grube, Susanne;Duenisch, Pedro;Ewald, Christian
脂肪酸合成酶（FASN），催化脂肪酸的从头合成，已知在几种癌症中不受控制。抑制这种酶可减少肿瘤细胞的增殖。不幸的是，副作用和化学不稳定性阻碍了最著名的抑制剂Cerulenin和C75在体内的使用。奥利司他，一种用于治疗肥胖的药物，也被认为是一种潜在的FASN抑制剂，但其对胶质瘤细胞生物学的影响尚未被描述。在本研究中，我们分析了FASN在人胶质瘤样本和原代胶质母细胞瘤细胞培养中的表达，以及奥利司他、Cerulenin和C75对FASN的抑制作用。免疫组织化学随后对20个胶质瘤样本进行密度分析，结果显示FASN过表达与WHO肿瘤分级相关。用这些抑制剂治疗胶质母细胞瘤细胞导致肿瘤细胞活力和脂肪酸合成显著的剂量依赖性降低。与Cerulenin和C75相比，奥利司他在细胞培养和细胞系中是更有效的抑制剂。在LN229中，与对照组相比，使用200 μ M奥利司他48 h后细胞生长减少了63.9 +/- 8.7%；在LT68中，细胞生长减少76.3 +/- A 23.7%。奥利司他靶向FASN后，核碎片分析和Western blotting分析显示自噬和凋亡。奥利司他处理的器官型切片培养在Ki67染色后显示增殖减少，caspase-3切割增加。我们的研究结果表明FASN可能是恶性胶质瘤的治疗靶点，并确定奥利司他可能是一种抗肿瘤药物。
Fatty acid synthase (FASN), catalyzing the de novo synthesis of fatty acids, is known to be deregulated in several cancers. Inhibition of this enzyme reduces tumor cell proliferation. Unfortunately, adverse effects and chemical instability prevent the in vivo use of the best-known inhibitors, Cerulenin and C75. Orlistat, a drug used for obesity treatment, is also considered as a potential FASN inhibitor, but its impact on glioma cell biology has not yet been described. In this study, we analyzed FASN expression in human glioma samples and primary glioblastoma cell cultures and the effects of FASN inhibition with Orlistat, Cerulenin and C75. Immunohistochemistry followed by densitometric analysis of 20 glioma samples revealed overexpression of FASN that correlated with the WHO tumor grade. Treatment of glioblastoma cells with these inhibitors resulted in a significant, dose-dependent reduction in tumor cell viability and fatty acid synthesis. Compared to Cerulenin and C75, Orlistat was a more potent inhibitor in cell cultures and cell lines. In LN229, cell-growth was reduced by 63.9 +/- A 8.7 % after 48 h and 200 A mu M Orlistat compared to controls; in LT68, the reduction in cell growth was 76.3 +/- A 23.7 %. Nuclear fragmentation assay and Western blotting analysis after targeting FASN with Orlistat demonstrated autophagy and apoptosis. Organotypic slice cultures treated with Orlistat showed reduced proliferation after Ki67 staining and increased caspase-3 cleavage. Our results suggest that FASN may be a therapeutic target in malignant gliomas and identify Orlistat as a possible anti-tumor drug in this setting.