In search of druggable targets for GBM amino acid metabolism.
In search of druggable targets for GBM amino acid metabolism.
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DOI：
10.1186/s12885-017-3148-1
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发表时间：
2017-02-28
期刊：
影响因子：
3.8
通讯作者：
Lasky JL 3rd
中科院分区：
文献类型：
--
作者：
Panosyan EH;Lin HJ;Koster J;Lasky JL 3rd
氨基酸（AA）途径可能包含胶质母细胞瘤（GBM）的药物靶点。进行文献综述和GBM数据库（http：r2.amc.nl）分析以在95种AA相关酶中筛选此类靶标。首先，我们鉴定了与非GBM脑组织（5个数据集）相比，GBM（3个数据集）中差异表达的基因，或者与生存差异相关的基因。此外，还在高级别神经胶质瘤（HGG）中分析了这些酶的蛋白质表达（proteinatlas.org）。最后，在GBM的4个TCGA（癌症基因组图谱）亚型之间比较AA酶和基因表达。我们检测到GBM中参与谷氨酸和尿素循环代谢的酶的差异。例如，在GBM中，BCAT 1（支链氨基酸转移酶1）和ASL（氨基琥珀酸裂解酶）的表达水平高，但ASS 1（氨基琥珀酸合成酶1）的表达水平低。前神经和神经TCGA亚型的所有三个低表达。这三种基因的高表达与不良预后相关。ASL和ASS 1蛋白水平在高级别胶质瘤中大多未检测到，而BCAT 1蛋白水平较高。GSS（谷胱甘肽合成酶）没有差异表达，但较高的水平与无进展生存率相关。ASPA（谷氨酸酰化酶）和GOT 1（谷草转氨酶1）在GBM中的表达较低（与不良结局相关）。所有三种GABA相关基因-谷氨酸脱羧酶1（GAD 1）和2（GAD 2）和4-氨基丁酸转氨酶（ABAT）-在间叶肿瘤中均较低，相反，IDO 1（吲哚胺2，3-双加氧酶1）和TDO 2（色氨酸2，3-双加氧酶）较高。GBM中脯氨酸脱氢酶（PRODH）的表达较低，这是一种假定的肿瘤抑制因子。较高的水平预示着较差的生存率。GBM中较高的几种AA代谢酶也与不良结局相关（如BCAT 1），这使其成为治疗抑制的潜在靶点。此外，现有的消耗天冬酰胺和精氨酸的药物可能对脑肿瘤有效，应该与化疗联合研究。最后，GBM的TCGA亚型（以及髓母细胞瘤和其他儿科肿瘤）中AA代谢是异质性的，这可能会转化为对AA靶向治疗的不同反应。本文的在线版本（doi：10.1186/s12885-017-3148-1）包含补充材料，可供授权用户使用。
Amino acid (AA) pathways may contain druggable targets for glioblastoma (GBM). Literature reviews and GBM database (http://r2.amc.nl) analyses were carried out to screen for such targets among 95 AA related enzymes. First, we identified the genes that were differentially expressed in GBMs (3 datasets) compared to non-GBM brain tissues (5 datasets), or were associated with survival differences. Further, protein expression for these enzymes was also analyzed in high grade gliomas (HGGs) (proteinatlas.org). Finally, AA enzyme and gene expression were compared among the 4 TCGA (The Cancer Genome Atlas) subtypes of GBMs. We detected differences in enzymes involved in glutamate and urea cycle metabolism in GBM. For example, expression levels of BCAT1 (branched chain amino acid transferase 1) and ASL (argininosuccinate lyase) were high, but ASS1 (argininosuccinate synthase 1) was low in GBM. Proneural and neural TCGA subtypes had low expression of all three. High expression of all three correlated with worse outcome. ASL and ASS1 protein levels were mostly undetected in high grade gliomas, whereas BCAT1 was high. GSS (glutathione synthetase) was not differentially expressed, but higher levels were linked to poor progression free survival. ASPA (aspartoacylase) and GOT1 (glutamic-oxaloacetic transaminase 1) had lower expression in GBM (associated with poor outcomes). All three GABA related genes -- glutamate decarboxylase 1 (GAD1) and 2 (GAD2) and 4-aminobutyrate aminotransferase (ABAT) -- were lower in mesenchymal tumors, which in contrast showed higher IDO1 (indoleamine 2, 3-dioxygenase 1) and TDO2 (tryptophan 2, 3-diaxygenase). Expression of PRODH (proline dehydrogenase), a putative tumor suppressor, was lower in GBM. Higher levels predicted poor survival. Several AA-metabolizing enzymes that are higher in GBM, are also linked to poor outcome (such as BCAT1), which makes them potential targets for therapeutic inhibition. Moreover, existing drugs that deplete asparagine and arginine may be effective against brain tumors, and should be studied in conjunction with chemotherapy. Last, AA metabolism is heterogeneous in TCGA subtypes of GBM (as well as medulloblastomas and other pediatric tumors), which may translate to variable responses to AA targeted therapies. The online version of this article (doi:10.1186/s12885-017-3148-1) contains supplementary material, which is available to authorized users.