Understanding the glutaminase functional regulation and the development of inhibitors as new approaches to cancer therapy

• Grant number: 14/15968-3
• Support Opportunities: Regular Research Grants
• Duration: November 01, 2014 - October 31, 2016
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Sandra Martha Gomes Dias
• Grantee: Sandra Martha Gomes Dias
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Associated researchers: Andre Luis Berteli Ambrosio

Abstract

Cell proliferation is a crucial process for the embryogenesis and organism growth, being also essential for the proper function of several adult tissues. Although important for the homeostasis of the organism, its deregulation composes the driving force of tumor development. In the past twenty years the relationship between the processes of signal transduction stimulated by growth factors and the reorganization of metabolic activity has become more evident. Growing cells need to prioritize the biosynthesis and biomass increasing, processes essential for cell division. In tumor cells, the glutamine consumption is increased concurrently with the increasing in the glutaminase activity. The enhanced glucose intake and metabolism, associated to the lactate secretion, even when in presence of oxygen (called aerobic glycolysis or Warburg Effect) followed by the intensification of the glutaminolisis are already recognized hallmarks of cell transformaton. These processess are closelly related to the tumor cells bioenergetic and bissynthetics needs since they provide with the metabolites involved on protein, lipids and nucleic acid synthesis. Although MYC regulation of the glutaminase activity is already well documented, our lab results have been showing that the mTORC1 and NFkB signaling pathways also regulates glutaminase activity. The first goal of this project is to understand these exact regulation mechanisms. Several studies, including from our lab's, revealed that several tumor types are higly dependent on the glutamine consumption which puts this enzyme as an important target againts cancer. The second goal of this project is to deepen the knowledge on the molecular and cellular mode of action of new glutaminase inhibitory compounds found in our lab after a Hight Throughput Screening campaing, which can represent the development of new and promissing anti-tumor drugs. On the other hand, some tumors do not respond to the glutamine consumption blockage, and searching for new molecular targets that can affect the aberrant tumor metabolism opened new therapeutic perspectives and composes the third goal of this project. (AU)

Scientific publications

(8)

(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)

SANTOS, CARLA C. F.; PARADELA, LUCIANA S.; NOVAES, LUIZ F. T.; DIAS, SANDRA M. G.; PASTRE, JULIO C.. Design and synthesis of cenocladamide analogues and their evaluation against breast cancer cell lines. MedChemComm, v. 8, n. 4, p. 755-766, APR 1 2017. (15/08199-6, 14/25770-6, 14/26378-2, 14/15968-3)

REDIS, ROXANA S.; VELA, LUZ E.; LU, WEIQIN; DE OLIVEIRA, JULIANA FERREIRA; IVAN, CRISTINA; RODRIGUEZ-AGUAYO, CRISTIAN; ADAMOSKI, DOUGLAS; PASCULLI, BARBARA; TAGUCHI, AYUMU; CHEN, YUNYUN; et al. Allele-Specific Reprogramming of Cancer Metabolism by the Long Non-coding RNA CCAT2. MOLECULAR CELL, v. 61, n. 4, p. 520-534, FEB 18 2016. (14/17820-3, 14/20673-2, 14/15968-3)

QUINTERO, MELISSA; ADAMOSKI, DOUGLAS; DOS REIS, LARISSA MENEZES; RODRIGUES ASCENCAO, CAROLLINE FERNANDA; SOUSA DE OLIVEIRA, KRISHINA RATNA; GONCALVES, KALIANDRA DE ALMEIDA; DIAS, MARILIA MEIRA; CARAZZOLLE, MARCELO FALSARELLA; GOMES DIAS, SANDRA MARTHA. Guanylate-binding protein-1 is a potential new therapeutic target for triple-negative breast cancer. BMC CANCER, v. 17, NOV 7 2017. (14/17820-3, 15/25832-4, 14/18061-9, 12/09452-9, 12/11577-4, 09/53853-5, 13/23510-4, 14/06512-6, 14/15968-3)

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, DEC 10 2021. (13/23510-4, 15/25832-4, 16/09077-4, 13/07600-3, 19/16351-3, 14/17820-3, 14/15968-3)

DOS REIS, LARISSA MENEZES; ADAMOSKI, DOUGLAS; OLIVEIRA SOUZA, RODOLPHO ORNITZ; RODRIGUES ASCENCAO, CAROLLINE FERNANDA; SOUSA DE OLIVEIRA, KRISHINA RATNA; CORREA-DA-SILVA, FELIPE; DE SA PATRONI, FABIO MALTA; DIAS, MARILIA MEIRA; CONSONNI, SILVIO ROBERTO; MENDES DE MORAES-VIEIRA, PEDRO MANOEL; et al. Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells. Journal of Biological Chemistry, v. 294, n. 24, p. 9342-9357, JUN 14 2019. (15/15626-8, 14/17820-3, 15/25832-4, 14/18061-9, 15/26059-7, 16/06034-2, 17/06225-5, 13/23510-4, 14/06512-6, 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., 2023-02-17. (13/07600-3, 16/09077-4, 21/13736-1, 14/26378-2, 19/16351-3, 20/12904-5, 21/06661-5, 14/15968-3)

DIAS, MARILIA M.; ADAMOSKI, DOUGLAS; DOS REIS, LARISSA M.; ASCENCAO, CAROLLINE F. R.; DE OLIVEIRA, KRISHINA R. S.; PASCHOALINI MAFRA, ANA CAROLINA; DA SILVA BASTOS, ALLINY CRISTINY; QUINTERO, MELISSA; CASSAGO, CAROLINA DE G.; FERREIRA, IGOR M.; et al. GLS2 is protumorigenic in breast cancers. Oncogene, v. 39, n. 3, p. 690-702, JAN 2020. (13/05668-0, 14/18061-9, 12/14298-9, 13/23510-4, 14/17820-3, 14/06512-6, 14/15968-3, 15/25832-4, 12/09452-9, 14/20673-2, 16/06625-0, 12/11577-4, 11/10127-2)

FALA, ANGELA M.; OLIVEIRA, JULIANA F.; ADAMOSKI, DOUGLAS; ARICETTI, JULIANA A.; DIAS, MARILIA M.; DIAS, MARCIO V. B.; SFORCA, MAURCIO L.; LOPES-DE-OLIVEIRA, PAULO S.; ROCCO, SILVANA A.; CALDANA, CAMILA; et al. Unsaturated fatty acids as high-affinity ligands of the C-terminal Per-ARNT-Sim domain from the Hypoxia-inducible factor 3 alpha. SCIENTIFIC REPORTS, v. 5, AUG 3 2015. (12/14298-9, 10/13739-6, 14/04927-4, 14/20673-2, 14/15968-3)