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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.)

GLS2 is protumorigenic in breast cancers

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Dias, Marilia M. [1, 2] ; Adamoski, Douglas [1, 2] ; dos Reis, Larissa M. [1, 2] ; Ascencao, Carolline F. R. [1, 2] ; de Oliveira, Krishina R. S. [1, 2] ; Paschoalini Mafra, Ana Carolina [1, 2] ; da Silva Bastos, Alliny Cristiny [1, 2] ; Quintero, Melissa [1] ; Cassago, Carolina de G. [1] ; Ferreira, Igor M. [1] ; Fidelis, V, Carlos H. ; Rocco, Silvana A. [1] ; Bajgelman, Marcio Chaim [1] ; Stine, Zachary [3] ; Berindan-Neagoe, Ioana [4, 5, 6] ; Calin, George A. [7, 8] ; Berteli Ambrosio, Andre Luis [1, 9] ; Gomes Dias, Sandra Martha [1]
Total Authors: 18
Affiliation:
[1] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, BR-13083970 Campinas, SP - Brazil
[2] Univ Estadual Campinas, Grad Program Genet & Mol Biol, Inst Biol, UNICAMP, Campinas, SP - Brazil
[3] Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 - USA
[4] Univ Med & Pharm Iuliu Hatieganu, Res Ctr Funct Genom Biomed & Translat Med, Cluj Napoca 400337 - Romania
[5] Univ Med & Pharm Iuliu Hatieganu, MedFuture Res Ctr Adv Med, Cluj Napoca 400349 - Romania
[6] Oncol Inst Prof Dr Ion Chiricuta, Dept Funct Genom & Expt Pathol, Cluj Napoca 400015 - Romania
[7] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, 1515 Holcombe Blvd, Unit 1950, Houston, TX 77030 - USA
[8] Univ Texas MD Anderson Canc Ctr, Ctr RNA Inference & Noncoding RNAs, 1515 Holcombe Blvd, Unit 1950, Houston, TX 77030 - USA
[9] Univ Sao Paulo, Sao Carlos Inst Phys IFSC, BR-13563120 Sao Carlos, SP - Brazil
Total Affiliations: 9
Document type: Journal article
Source: Oncogene; v. 39, n. 3, p. 690-702, JAN 2020.
Web of Science Citations: 0
Abstract

Many types of cancers have a well-established dependence on glutamine metabolism to support survival and growth, a process linked to glutaminase 1 (GLS) isoforms. Conversely, GLS2 variants often have tumor-suppressing activity. Triple-negative (TN) breast cancer (testing negative for estrogen, progesterone, and Her2 receptors) has elevated GLS protein levels and reportedly depends on exogenous glutamine and GLS activity for survival. Despite having high GLS levels, we verified that several breast cancer cells (including TN cells) express endogenous GLS2, defying its role as a bona fide tumor suppressor. Moreover, ectopic GLS2 expression rescued cell proliferation, TCA anaplerosis, redox balance, and mitochondrial function after GLS inhibition by the small molecule currently in clinical trials CB-839 or GLS knockdown of GLS-dependent cell lines. In several cell lines, GLS2 knockdown decreased cell proliferation and glutamine-linked metabolic phenotypes. Strikingly, long-term treatment of TN cells with another GLS-exclusive inhibitor bis-2 `-(5-phenylacetamide-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) selected for a drug-resistant population with increased endogenous GLS2 and restored proliferative capacity. GLS2 was linked to enhanced in vitro cell migration and invasion, mesenchymal markers (through the ERK-ZEB1-vimentin axis under certain conditions) and in vivo lung metastasis. Of concern, GLS2 amplification or overexpression is linked to an overall, disease-free and distant metastasis-free worse survival prognosis in breast cancer. Altogether, these data establish an unforeseen role of GLS2 in sustaining tumor proliferation and underlying metastasis in breast cancer and provide an initial framework for exploring GLS2 as a novel therapeutic target. (AU)

FAPESP's process: 13/05668-0 - Understanding the mechanistic and functional details of the isozyme mammalian Liver-type glutaminase (LGA/GLS2)
Grantee:Igor Monteze Ferreira
Support type: Scholarships in Brazil - Doctorate (Direct)
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: 12/14298-9 - Cancer metabolic adaptation: structural and functional studies of key proteins
Grantee:Andre Luis Berteli Ambrosio
Support type: Regular Research Grants
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: 12/09452-9 - Transcriptome and metabolomic studies of cancer cells as a tool for understanding the metabolic adaptation process
Grantee:Melissa Quintero Escobar
Support type: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 14/20673-2 - Biophysical and biochemical studies of the mitochondrial pyruvate carrier (MPC) complex and the glutaminase enzyme bound to novel partners
Grantee:Andre Luis Berteli Ambrosio
Support type: Regular Research Grants
FAPESP's process: 16/06625-0 - The mechanisms underlying the GLS2 pro-tumorigenic role
Grantee:Ana Carolina Paschoalini Mafra
Support type: Scholarships in Brazil - Doctorate (Direct)
FAPESP's process: 12/11577-4 - Studies of the metabolic alterations related to the PI3K-AKT pathway and ras oncogene co-activation
Grantee:Marília Meira Dias
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 11/10127-2 - Studies of the nuclear location and nuclear receptor interaction of glutaminases
Grantee:Carolina Aparecida de Guzzi Cassago
Support type: Scholarships in Brazil - Doctorate