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The glutaminase role on tumor progression


Cancer is a disease that has as main characteristic the continuous cellular proliferation. To support the high proliferative rate, tumor cells have increased demand for biosynthetic precursors used in the synthesis of macromolecules that will make up the daughter cells. For that, tumors consume a lot of glucose and glutamine, mainly. The increase in glutamine consumption, in addition to contributing to the formation of biosynthetic precursors, is related to tumor progression, providing a malignancy gain. The enzyme that catabolizes glutamine into glutamate, glutaminase, is encoded by two genes, GLS and GLS2. In addition to possessing glutaminase domain, both isoenzymes also have extra domains involved in contact with other proteins; the function of these interactions is only partially understood. The pro-oncogenic role of GLS has been shown by several works in a unanimous manner. In contrast, GLS2 has shown to play an ambiguous role, behaving as tumor suppressor in some contexts and pro-tumoral in others. Recent findings from our research group point to a pro-tumor role of GLS2 in breast tumors. Specifically, we found that a fraction of patients with greater GLS2 expression had worse prognosis; Introduction of GLS2 in cell lines accentuates or leads to mesenchymal epithelium transition, invasive capacity in vitro and pulmonary metastasis in vivo, in addition to other findings. Bioinformatics analyzes between breast tumors with high versus low GLS2 expression revealed several pathways potentially involved with the increased invasive and metastasis. In particular, in silico analyzes using CIBERSORT have identified the potential for infiltration of cells of the immune system that may be contributing to a worse prognosis. We intend to evaluate if the ectopic GLS2 expression (or its knockdown) is related to increased invasion of cell lines in vitro, as well as its interaction with specific cells of the immune system. Finally, we will try to identify, by immunoprecipitation assay followed by mass spectrometry, proteins that interact with GLS2 and which could be linked to the metastatic process. Thus, objective 1 of this project is to confirm the pro-tumor role of GLS2 in breast cancer and to understand it from a mechanistic point of view. Double-hybrid studies in yeast previously performed in the laboratory showed that glycolytic enzymes enolase 1 (ENO1) and pyruvate kinase M2 (PKM2) are potential binding partners of GLS, GAC and KGA isoforms. We have expressed PKM2 in a heterologous system, purifyed it and shown, by pull-down and fluorescence anisotropy, that it interacted directly with GAC. In addition, GAC and PKM2 expressed ectopically in mammalian cells co-immunoprecipitated and showed signs of mitochondrial co-localization. The objective of this work is to confirm the interaction of the KGA and GAC isoforms with PKM2 and to deepen the biochemical description of the findings, as well as its importance for the cellular phenotypes of glutamine metabolism, proliferation and invasion. We will also characterize the interaction of GAC and KGA with ENO1, following similar techniques. Thus, objective 2 of this project is to elucidate novel pathways of GAC and KGA enzymes via interaction with glycolytic enzymes and their importance for tumor development, with potential implication in the development of new therapies. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CIOCAN-CARTITA, CRISTINA ALEXANDRA; JURJ, ANCUTA; ZANOAGA, OANA; COJOCNEANU, ROXANA; POP, LAURA-ANCUTA; MOLDOVAN, ALIN; MOLDOVAN, CRISTIAN; ZIMTA, ALINA ANDREEA; RADULY, LAJOS; POP-BICA, CECILIA; et al. New insights in gene expression alteration as effect of doxorubicin drug resistance in triple negative breast cancer cells. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH, v. 39, n. 1, . (19/16351-3)
COSTA, RENNA K. E.; RODRIGUES, CAMILA T.; CAMPOS, JEAN C. H.; PARADELA, LUCIANA S.; DIAS, MARILIA M.; DA SILVA, BIANCA NOVAES; DE VALEGA NEGRAO, CYRO VON ZUBEN; GONCALVES, KALIANDRA DE ALMEIDA; ASCENCAO, CAROLLINE F. R.; ADAMOSKI, DOUGLAS; et al. High-Throughput Screening Reveals New Glutaminase Inhibitor Molecules. ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE, v. 4, n. 6, p. 1849-1866, . (13/23510-4, 15/25832-4, 16/09077-4, 13/07600-3, 19/16351-3, 14/17820-3, 14/15968-3)
COSTA, RENNA K. E.; BRANCAGLION, GUILHERME A.; PINHEIRO, MATHEUS P.; ADAMOSKI, DOUGLAS; DA SILVA, BIANCA N.; NEGRAO, CYRO Z. DE V.; GONCALVES, KALIANDRA DE A.; RODRIGUES, CAMILA T.; AMBROSIO, ANDRE L. B.; GUIDO, RAFAEL V. C.; et al. Discovery of aminothiazole derivatives as a chemical scaffold for glutaminase inhibition. RESULTS IN CHEMISTRY, v. 5, p. 17-pg., . (13/07600-3, 16/09077-4, 21/13736-1, 14/26378-2, 19/16351-3, 20/12904-5, 21/06661-5, 14/15968-3)

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