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Moreira Franco, Yollanda E.
[1]
;
Alves, Maria Jose
[1]
;
Uno, Miyuki
[1]
;
Moretti, Isabele Fattori
[1]
;
Trombetta-Lima, Marina
[2, 1]
;
de Siqueira Santos, Suzana
[3]
;
dos Santos, Ancely Ferreira
[4]
;
Arini, Gabriel Santos
[4]
;
Baptista, Mauricio S.
[4]
;
Lerario, Antonio Marcondes
[5]
;
Oba-Shinjo, Sueli Mieko
[1]
;
Marie, Suely Kazue Nagahashi
[1]
Número total de Autores: 12
|
| Afiliação do(s) autor(es): | [1] Univ Sao Paulo, Dept Neurol, Lab Mol & Cellular Biol LIM 15, Fac Med FMUSP, BR-01246903 Sao Paulo - Brazil
[2] Univ Groningen, Dept Mol Pharmacol, NL-9713 AV Groningen - Netherlands
[3] Fundacao Getulio Vargas, Sch Appl Math, BR-22250900 Rio De Janeiro - Brazil
[4] Univ Sao Paulo, Inst Chem, Dept Biochem, BR-05508000 Sao Paulo - Brazil
[5] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 - USA
Número total de Afiliações: 5
|
| Tipo de documento: | Artigo Científico |
| Fonte: | CANCER & METABOLISM; v. 9, n. 1 APR 28 2021. |
| Citações Web of Science: | 0 |
| Resumo | |
Background Glioblastoma is the most frequent and high-grade adult malignant central nervous system tumor. The prognosis is still poor despite the use of combined therapy involving maximal surgical resection, radiotherapy, and chemotherapy. Metabolic reprogramming currently is recognized as one of the hallmarks of cancer. Glutamine metabolism through glutaminolysis has been associated with tumor cell maintenance and survival, and with antioxidative stress through glutathione (GSH) synthesis. Methods In the present study, we analyzed the glutaminolysis-related gene expression levels in our cohort of 153 astrocytomas of different malignant grades and 22 non-neoplastic brain samples through qRT-PCR. Additionally, we investigated the protein expression profile of the key regulator of glutaminolysis (GLS), glutamate dehydrogenase (GLUD1), and glutamate pyruvate transaminase (GPT2) in these samples. We also investigated the glutathione synthase (GS) protein profile and the GSH levels in different grades of astrocytomas. The differential gene expressions were validated in silico on the TCGA database. Results We found an increase of glutaminase isoform 2 gene (GLSiso2) expression in all grades of astrocytoma compared to non-neoplastic brain tissue, with a gradual expression increment in parallel to malignancy. Genes coding for GLUD1 and GPT2 expression levels varied according to the grade of malignancy, being downregulated in glioblastoma, and upregulated in lower grades of astrocytoma (AGII-AGIII). Significant low GLUD1 and GPT2 protein levels were observed in the mesenchymal subtype of GBM. Conclusions In glioblastoma, particularly in the mesenchymal subtype, the downregulation of both genes and proteins (GLUD1 and GPT2) increases the source of glutamate for GSH synthesis and enhances tumor cell fitness due to increased antioxidative capacity. In contrast, in lower-grade astrocytoma, mainly in those harboring the IDH1 mutation, the gene expression profile indicates that tumor cells might be sensitized to oxidative stress due to reduced GSH synthesis. The measurement of GLUD1 and GPT2 metabolic substrates, ammonia, and alanine, by noninvasive MR spectroscopy, may potentially allow the identification of IDH1(mut) AGII and AGIII progression towards secondary GBM. (AU) | |
| Processo FAPESP: | 13/02162-8 - Patogênese molecular e caracterização de doenças monogênicas do desenvolvimento: um caminho para a medicina translacional |
| Beneficiário: | Berenice Bilharinho de Mendonça |
| Modalidade de apoio: | Auxílio à Pesquisa - Temático |
| Processo FAPESP: | 20/02988-7 - Decodificando o impacto do microambiente e das vias de sinalização na saúde e na doença no cérebro, glândula adrenal e rim |
| Beneficiário: | Suely Kazue Nagahashi Marie |
| Modalidade de apoio: | Auxílio à Pesquisa - Temático |
| Processo FAPESP: | 15/26328-8 - Análise comparativa do papel do gene supressor de tumor RECK na sub-população de células-tronco tumorais de GBM e em precursores neurais normais. |
| Beneficiário: | Marina Trombetta Lima |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |
| Processo FAPESP: | 01/12898-4 - Genoma clínico |
| Beneficiário: | Suely Kazue Nagahashi Marie |
| Modalidade de apoio: | Auxílio à Pesquisa - Programa GENOMA |
| Processo FAPESP: | 13/07937-8 - Redoxoma |
| Beneficiário: | Ohara Augusto |
| Modalidade de apoio: | Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs |
| Processo FAPESP: | 04/12133-6 - Procura de marcadores moleculares relacionados ao diagnóstico e prognóstico de tumores do sistema nervoso central |
| Beneficiário: | Suely Kazue Nagahashi Marie |
| Modalidade de apoio: | Auxílio à Pesquisa - Temático |