| Full text | |
| Author(s): Show less - |
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]
Total Authors: 12
|
| Affiliation: | [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
Total Affiliations: 5
|
| Document type: | Journal article |
| Source: | CANCER & METABOLISM; v. 9, n. 1 APR 28 2021. |
| Web of Science Citations: | 0 |
| Abstract | |
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) | |
| FAPESP's process: | 13/02162-8 - Molecular pathogenesis and characterization of monogenic developmental diseases: a route to translational medicine |
| Grantee: | Berenice Bilharinho de Mendonça |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 20/02988-7 - Decoding the impact of microenvironment and signaling pathways in health and disease in brain, adrenal gland and kidney |
| Grantee: | Suely Kazue Nagahashi Marie |
| Support Opportunities: | Research Projects - Thematic Grants |
| FAPESP's process: | 15/26328-8 - Comparative analysis of the Reck tumor suppressor gene role in glioblastoma stem cell sub-population and in normal neural stem cells. |
| Grantee: | Marina Trombetta Lima |
| Support Opportunities: | Scholarships in Brazil - Post-Doctoral |
| FAPESP's process: | 13/07937-8 - Redoxome - Redox Processes in Biomedicine |
| Grantee: | Ohara Augusto |
| Support Opportunities: | Research Grants - Research, Innovation and Dissemination Centers - RIDC |
| FAPESP's process: | 04/12133-6 - Search for molecular markers related to the diagnosis and prognosis of tumors of the central nervous system |
| Grantee: | Suely Kazue Nagahashi Marie |
| Support Opportunities: | Research Projects - Thematic Grants |