| Grant number: | 16/06625-0 |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |
| Effective date (Start): | July 01, 2016 |
| Effective date (End): | June 30, 2021 |
| Field of knowledge: | Biological Sciences - Biochemistry - Chemistry of Macromolecules |
| Principal Investigator: | Sandra Martha Gomes Dias |
| Grantee: | Ana Carolina Paschoalini Mafra |
| Host Institution: | Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil |
| Associated scholarship(s): | 16/23301-4 - Glutaminase 2 influence on tumor: macrophage interaction and metastasis, BE.EP.DD |
Abstract Cancer is a disease in which its main characteristic is the continuous cell proliferation. To sustain the high proliferative rate, tumor cells have an increased demand for biosynthetic precursors used in the synthesis of macromolecules that compose the daughter cells. Therefore, tumors consume a large amount of glucose and glutamine, mainly. The increase in glutamine consumption, besides contributing to the formation of biosynthetic precursors, is related to tumor progression. The enzyme that metabolizes glutamine into glutamate, glutaminase, is encoded by two genes, GLS and GLS2. The pro-oncogenic role of GLS1 has been shown by several studies unanimously. In contrast, GLS2 has shown to have an ambiguous role, behaving as a tumor suppressor in certain contexts and pro-tumorigenic in others. Recent findings of the group, in which this proposal is part of, point to a pro-tumorigenic role of GLS2 in breast tumors. Specifically, bioinformatical analysis of patient breast tumors obtained from The Cancer Genome Atlas platform (TCGA) showed worse survival in patients whose tumors had higher expression of GLS2, compared to patients with high expression of GLS or no change in expression of glutaminases. When evaluating genes differentially expressed between tumor tissues with high expression of GLS2 versus tissues with low expression GLS2, identified by the MetaCore software, various routes potentially involved in tumor progression were significantly affected. Among them, pathways that can enhance the invasive and metastatic potential of tumors. In addition, we found that strains of subtype basal-like TN cell lines, more aggressive, have increased expression of GLS2. Finally, preliminary studies with xenografts showed that ectopic expression of GLS2 (isoform GAB) enhanced the formation of lung metastasis from the MDA-MB-231 cell line. Bearing these observations in mind, the main objective of this study is to investigate whether there is a relationship between increased GLS2 expression (or its knockdown) with the expression of the genes identified in the pathways described by MetaCore, using cell lines as models. In addition, we will check if the ectopic expression of GLS2 (or its knockdown) is related to the invasive potential of strains using in vitro study models. Finally, we seek to identify by immunoprecipitation followed by mass spectrometry proteins that interact with GLS2 and could be linked to the process of metastasis. We intend to identify with this work the mechanism behind the pro-tumorigenic action of GLS2 in breast tumors, information that may be useful to outline future therapies. (AU) | |
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