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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells

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dos Reis, Larissa Menezes [1, 2] ; Adamoski, Douglas [1, 2] ; Oliveira Souza, Rodolpho Ornitz [3] ; Rodrigues Ascencao, Carolline Fernanda [1, 2] ; Sousa de Oliveira, Krishina Ratna [1, 2] ; Correa-da-Silva, Felipe [2, 4] ; de Sa Patroni, Fabio Malta [1, 2] ; Dias, Marilia Meira [1] ; Consonni, Silvio Roberto [5] ; Mendes de Moraes-Vieira, Pedro Manoel [4] ; Silber, Ariel Mariano [3] ; Gomes Dias, Sandra Martha [1]
Total Authors: 12
[1] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, BR-13083970 Campinas, SP - Brazil
[2] Univ Estadual Campinas, Inst Biol, Grad Program Genet & Mol Biol, BR-13083970 Campinas, SP - Brazil
[3] Univ Sao Paulo, Inst Biomed Sci, Dept Parasitol, Lab Biochem Tryps, BR-05508000 Sao Paulo, SP - Brazil
[4] Univ Estadual Campinas, Inst Biol, Lab Immunometab, Dept Genet Evolut Microbiol & Immunol, BR-13083970 Campinas, SP - Brazil
[5] Univ Estadual Campinas, Inst Biol, Dept Biochem & Tissue Biol, Lab Cytochem & Immunocytochem, BR-13083970 Campinas, SP - Brazil
Total Affiliations: 5
Document type: Journal article
Source: Journal of Biological Chemistry; v. 294, n. 24, p. 9342-9357, JUN 14 2019.
Web of Science Citations: 3

Triple-negative breast cancers (TNBCs) lack progesterone and estrogen receptors and do not have amplified human epidermal growth factor receptor 2, the main therapeutic targets for managing breast cancer. TNBCs have an altered metabolism, including an increased Warburg effect and glutamine dependence, making the glutaminase inhibitor CB-839 therapeutically promising for this tumor type. Accordingly, CB-839 is currently in phase I/II clinical trials. However, not all TNBCs respond to CB-839 treatment, and the tumor resistance mechanism is not yet fully understood. Here we classified cell lines as CB-839-sensitive or -resistant according to their growth responses to CB-839. Compared with sensitive cells, resistant cells were less glutaminolytic and, upon CB-839 treatment, exhibited a smaller decrease in ATP content and less mitochondrial fragmentation, an indicator of poor mitochondrial health. Transcriptional analyses revealed that the expression levels of genes linked to lipid metabolism were altered between sensitive and resistant cells and between breast cancer tissues (available from The Cancer Genome Atlas project) with low versus high glutaminase (GLS) gene expression. Of note, CB-839-resistant TNBC cells had increased carnitine palmitoyltransferase 2 (CPT2) protein and CPT1 activity levels. In agreement, CB-839-resistant TNBC cells mobilized more fatty acids into mitochondria for oxidation, which responded to AMP-activated protein kinase and acetyl-CoA carboxylase signaling. Moreover, chemical inhibition of both glutaminase and CPT1 decreased cell proliferation and migration of CB-839-resistant cells compared with single inhibition of each enzyme. We propose that dual targeting of glutaminase and CPT1 activities may have therapeutic relevance for managing CB-839-resistant tumors. (AU)

FAPESP's process: 14/18061-9 - Study of alternative anaplerotic sources of the TCA as new targets against triple-negative breast cancer
Grantee:Larissa Menezes dos Reis
Support type: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 15/26059-7 - Identification of genes regulated by the several HIF-3a isoforms: development of tumor patients transcriptomics data analysis tool
Grantee:Fábio Malta de Sá Patroni
Support type: Scholarships in Brazil - Master
FAPESP's process: 13/23510-4 - Understanding how PI3K/AKT/mTOR and AMPK signaling pathways affect glutaminase activity
Grantee:Carolline Fernanda Rodrigues Ascenção
Support type: Scholarships in Brazil - Doctorate
FAPESP's process: 14/17820-3 - Post-transcriptional regulation of glutaminase enzyme by HuR and its relationship with high glutaminolytic levels in tumors
Grantee:Douglas Adamoski Meira
Support type: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 14/06512-6 - Epigenetic study of histone demethylases enzymes Fe (II) and ±-ketoglutarate dependent of the jumonji family in the context of tumoral metabolism and glutaminase activity
Grantee:Krishina Ratna Sousa de Oliveira
Support type: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 14/15968-3 - Understanding the glutaminase functional regulation and the development of inhibitors as new approaches to cancer therapy
Grantee:Sandra Martha Gomes Dias
Support type: Regular Research Grants
FAPESP's process: 15/25832-4 - Metabolic regulation of genetic and epigenetic control of gene expression
Grantee:Sandra Martha Gomes Dias
Support type: Regular Research Grants
FAPESP's process: 15/15626-8 - Macrophages and T lymphocytes immunometabolism in metabolic and inflammatory diseases
Grantee:Pedro Manoel Mendes de Moraes Vieira
Support type: Research Grants - Young Investigators Grants
FAPESP's process: 16/06034-2 - The biological role of amino acids and their metabolites in Trypanosoma cruzi
Grantee:Ariel Mariano Silber
Support type: Research Projects - Thematic Grants
FAPESP's process: 17/06225-5 - Influence of synthetic ([Nle 4, D-Phe7] -±-MSH on microglia metabolism: possible implications on obesity development
Grantee:Felipe Corrêa da Silva
Support type: Scholarships in Brazil - Master