GLS2 is protumorigenic in breast cancers

• Published in: Oncogene Vol. 39; no. 3; pp. 690 - 702
• Main Authors: Dias, Marilia M., Adamoski, Douglas, dos Reis, Larissa M., Ascenção, Carolline F. R., de Oliveira, Krishina R. S., Mafra, Ana Carolina Paschoalini, da Silva Bastos, Alliny Cristiny, Quintero, Melissa, de G. Cassago, Carolina, Ferreira, Igor M., Fidelis, Carlos H. V., Rocco, Silvana A., Bajgelman, Marcio Chaim, Stine, Zachary, Berindan-Neagoe, Ioana, Calin, George A., Ambrosio, Andre Luis Berteli, Dias, Sandra Martha Gomes
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.01.2020; Nature Publishing Group
• Subjects: 13/1; 13/31; 13/51; 13/89; 13/95; 14/19; 14/34; 14/63; 38/44; 38/70; 38/77; 38/91; 42/109; 631/67/1347; 631/67/322; 631/80/83; 64/60; Acetanilide; Adult; Aged; Aged, 80 and over; Apoptosis; Benzeneacetamides - pharmacology; Benzeneacetamides - therapeutic use; Breast - pathology; Breast - surgery; Breast cancer; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Breast Neoplasms - therapy; Carcinogenesis - pathology; Cell adhesion & migration; Cell Biology; Cell growth; Cell Line, Tumor; Cell migration; Cell proliferation; Clinical trials; Disease-Free Survival; Drug resistance; ErbB-2 protein; Female; Gene Knockdown Techniques; Glutaminase; Glutaminase - antagonists & inhibitors; Glutaminase - metabolism; Glutamine; Hormones, Sex; Human Genetics; Humans; Internal Medicine; Isoforms; Lung cancer; Lung Neoplasms - secondary; Medical prognosis; Medicine; Medicine & Public Health; Mesenchyme; Metastases; Metastasis; Middle Aged; Mitochondria; Oncology; Phenotypes; Physiological aspects; Progesterone; Prognosis; Sulfides; Sulfides - pharmacology; Sulfides - therapeutic use; Therapeutic applications; Thiadiazoles - pharmacology; Thiadiazoles - therapeutic use; Tumor suppressor genes; Vimentin; Romania
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-019-1007-z

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.