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.