Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

Abstract

Key Points• Myeloma cells produce ammonium in the presence of glutamine, showing high glutaminase and low glutamine synthetase expression.• Myeloma cells show high expression of glutamine transporters and inhibition of ASCT2 transporter hinders myeloma growth.The importance of glutamine (Gln) metabolism in multiple myeloma (MM) cells and its potential role as a therapeutic target are still unknown, although it has been reported that human myeloma cell lines (HMCLs) are highly sensitive to Gln depletion. In this study, we found that both HMCLs and primary bone marrow (BM) CD138 1 cells produced large amounts of ammonium in the presence of Gln. MM patients have lower BM plasma Gln with higher ammonium and glutamate than patients with indolent monoclonal gammopathies. Interestingly, HMCLs expressed glutaminase (GLS1) and were sensitive to its inhibition, whereas they exhibited negligible expression of glutamine synthetase (GS). High GLS1 and low GS expression were also observed in primary CD138 1 cells. Gln-free incubation or treatment with the glutaminolytic enzyme L-asparaginase depleted the cell contents of Gln, glutamate, and the anaplerotic substrate 2-oxoglutarate, inhibiting MM cell growth. Consistent with the dependence of MM cells on extracellular Gln, a gene expression profile analysis, on both proprietary and published datasets, showed an increased expression of the Gln transporters SNAT1, ASCT2, and LAT1 by CD138 1 cells across the progression of monoclonal gammopathies. Among these transporters, only ASCT2 inhibition in HMCLs caused a marked decrease in Gln uptake and a significant fall in cell growth. Consistently, stable ASCT2 downregulation by a lentiviral approach inhibited HMCL growth in vitro and in a murine model. In conclusion, MM cells strictly depend on extracellular Gln and show features of Gln addiction. Therefore, the inhibition of Gln uptake is a new attractive therapeutic strategy for MM. (Blood. 2016;128(5):667-679)

Glutaminase inhibitor CB-839 synergizes with carfilzomib in resistant multiple myeloma cells

“…While previous studies investigating the effects of CB-839 have demonstrated similar activity between CB-839 treatment and glutamine deprivation in cancer cells [13, 26, 42], our study differs fundamentally in that we were specifically investigating the activity of CB-839 in combination with PIs. We speculate that CB-839 induces a specific set of molecular effects that diverges from those induced by withdrawing all or part of glutamine from cells.…”

“…Recently, it has been demonstrated that MM cells lack expression of glutamine synthetase and display an increased expression of glutaminase 1 (GLS1), suggesting that these cells rely exclusively on extracellular glutamine for cellular energy [13]. GLS catalyzes the conversion of glutamine to glutamate, which supports redox balance through glutathione biosynthesis, and serves as a major substrate for the mitochondrial tricarboxylic acid (TCA) cycle [14–16].…”

Glutamine-derived 2-hydroxyglutarate is associated with disease progression in plasma cell malignancies

“…In most cases, overexpression of the transcription factor c-MYC is believed to drive progression of MGUS and SMM to MM (8). c-MYC also regulates glutamine metabolism by increasing glutamine anaplerosis into the TCA cycle of mitochondria (9), which is vital in clonal PCs from human myeloma cell lines (HMCLs) (10). 2-Hydroxyglutarate (2-HG), an oncometabolite derived from α-ketoglutarate in the TCA cycle, has been associated with epigenetic modifications causing tumorigenesis in cancers associated with IDH1/2 mutations such as acute myeloid leukemia (11,12) and glioblastoma (13).…”

Low-Dose Paclitaxel Inhibits Tumor Cell Growth by Regulating Glutaminolysis in Colorectal Carcinoma Cells

“…Tumor cell proliferation is susceptible to alterations in microenvironment pH (Bolzoni et al, 2016). To explore causes of reduced pH, we measured its lactate concentration, because lactate is a major source of acidity in cell metabolism (Seheult et al, 2017).…”

“…The glutamate dehydrogenase1 ( GDH ) encodes a trifunctional protein that is associated with the enzymatic activities of glutaminolysis (Koo and Yoon, 2015). The solute carrier family 1 member 5 ( SLC1A5 ) is related to glutamine uptake (Bolzoni et al, 2016). The solute carrier family 7 member 11 ( SLC7A11 ) is responsible for glutamate release in glutaminolysis (Kalivas, 2009).…”