Clinical aggressiveness of malignant gliomas is linked to augmented metabolism of amino acids - PubMed (original) (raw)

Clinical aggressiveness of malignant gliomas is linked to augmented metabolism of amino acids

Eduard H Panosyan et al. J Neurooncol. 2016 May.

Abstract

Glutamine, glutamate, asparagine, and aspartate are involved in an enzyme-network that controls nitrogen metabolism. Branched-chain-amino-acid aminotransferase-1 (BCAT1) promotes proliferation of gliomas with wild-type IDH1 and is closely connected to the network. We hypothesized that metabolism of asparagine, glutamine, and branched-chain-amino-acids is associated with progression of malignant gliomas. Gene expression for asparagine synthetase (ASNS), glutaminase (GLS), and BCAT1 were analyzed in 164 gliomas from 156 patients [33-anaplastic gliomas (AG) and 131-glioblastomas (GBM), 64 of which were recurrent GBMs]. ASNS and GLS were twofold higher in GBMs versus AGs. BCAT1 was also higher in GBMs. ASNS expression was twofold higher in recurrent versus new GBMs. Five patients had serial samples: 4-showed higher ASNS and 3-higher GLS at recurrence. We analyzed grade and treatment in 4 groups: (1) low ASNS, GLS, and BCAT1 (n = 96); (2) low ASNS and GLS, but high BCAT1 (n = 26); (3) high ASNS or GLS, but low BCAT1 (n = 25); and (4) high ASNS or GLS and high BCAT1 (n = 17). Ninety-one % of patients (29/32) with grade-III lesions were in group 1. In contrast, 95 % of patients (62/65) in groups 2-4 had GBMs. Treatment was similar in 4 groups (radiotherapy-80 %; temozolomide-30 %; other chemotherapy-50 %). High expression of ASNS, GLS, and BCAT1 were each associated with poor survival in the entire group. The combination of lower ASNS, GLS, and BCAT1 levels correlated with better survival for newly diagnosed GBMs (66 patients; P = 0.0039). Only tumors with lower enzymes showed improved outcome with temozolomide. IDH1(WT) gliomas had higher expression of these genes. Manipulation of amino acid metabolism in malignant gliomas may be further studied for therapeutics development.

Keywords: Asparagine; Branched chain amino acids; Glioma; Glutamine; Metabolism.

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Figures

Fig. 1

Fig. 1

Interplay of asparagine (ASN), glutamine (GLN), and branched-chain amino acids (BCAAs) in a metabolic network that affects mitochondrial energy production and nitrogen utilization. Other abbreviations: ASNS asparagine synthetase, ASP aspartate, BCAT1 branched chain amino-acid aminotransferase 1, BCKA branched chain ketoacids, GLU glutamate, GLS glutaminase, IC isocitrate, IDHWT isocitrate dehydrogenase, wild type, IDHMUT isocitrate dehydrogenase, mutated, 2HG 2-hydroxyglutarate, OA oxaloacetate

Fig. 2

Fig. 2

a Expression of asparagine synthetase (ASNS), glutaminase (GLS), and branched chain aminotransferases (BCAT1) in anaplastic gliomas (AG) versus glioblastomas (GBM), and expression of ASNS in newly diagnosed versus recurrent GBMs. GBMs have higher expression of all of these genes, compared to AGs. Recurrent GBMs have higher ASNS expression, compared to newly diagnosed GBMs. *P values (t test) are significant. b Asparagine synthetase (ASNS), glutaminase (GLS), and BCAT1, branched chain amino-acid aminotransferase expression in paired samples obtained from individual patients. ASNS expression was increased in 4 recurrences. GLS expression was increased in 3 recurrences. The horizontal axis indicates the diagnoses at dual surgeries, for each patient. AO, anaplastic oligodendroglioma; AMG, anaplastic mixed glioma, GBM, glioblastoma

Fig. 3

Fig. 3

Kaplan-Meier survival curves for 66 newly diagnosed GBMs in relation to expression of ASNS, GLS, and BCAT1, and to temozolomide (TMZ) treatment. a and b. Reduced overall survival (OS) and progression-free survival (PFS) of patients with newly diagnosed GBM whose tumors had higher expression of ASNS, GLS, and BCAT1. c and d. Increased OS and PFS with TMZ treatment in the low enzyme expression group only. Log rank P values are shown

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