Abstract
BackgroundAmino 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.MethodsFirst, 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.ResultsWe 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.ConclusionsSeveral 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.
Highlights
Amino acid (AA) pathways may contain druggable targets for glioblastoma (GBM)
Differential expression of enzyme genes in GBM and proteins in high grade gliomas (HGGs) Differential expression was defined as a ≥40% difference in gene expression for any gene, in GBM compared to non-GBM specimens
Fewer than 30 genes involved in AA metabolism met this criterion (Fig. 1)
Summary
Amino acid (AA) pathways may contain druggable targets for glioblastoma (GBM). In addition to surgery and radiation, brain tumors are subject to systemic therapies, which circulate in the bloodstream and affect cancer cells all over the body. The systemic therapies for cancer can be grouped into 4 main categories: (1) DNA damaging and/or repair suppressing agents [1] (e.g., cytotoxic chemotherapy); (2) cell signaling. In addition to the use of IDH1 and IDH2 inhibitors [12], targeting lipid [14] and carbohydrate (i.e., energy) metabolism has been an area of research (e.g., use of metformin [15]). Manipulation of amino acid metabolism remains an under-studied topic in current neuro-oncology research, and is the topic of this investigation
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