Glucose-Independent Glutamine Metabolism via TCA Cycling for Proliferation and Survival in B Cells

Abstract

Summary Because MYC plays a causal role in many human cancers, including those with hypoxic and nutrient-poor tumor microenvironments, we have determined the metabolic responses of a MYC-inducible human Burkitt lymphoma model P493 cell line to aerobic and hypoxic conditions, and to glucose deprivation, using Stable Isotope Resolved Metabolomics. Using [U-13C]-glucose as the tracer, both glucose consumption and lactate production were increased by MYC expression and hypoxia. Using [U-13C,15N]-glutamine as the tracer, glutamine import and metabolism through the TCA cycle persisted under hypoxia, and glutamine contributed significantly to citrate carbons. Under glucose deprivation, glutamine-derived fumarate, malate, and citrate were significantly increased. Their 13C labeling patterns demonstrate an alternative energy-generating glutaminolysis pathway involving a glucose-independent TCA cycle. The essential role of glutamine metabolism in cell survival and proliferation under hypoxia and glucose deficiency, makes them susceptible to the glutaminase inhibitor BPTES, and hence could be targeted for cancer therapy.

Let-7 Suppresses B Cell Activation through Restricting the Availability of Necessary Nutrients

“…Emerging evidence demonstrates that increased glycolysis and glutaminolysis are part of a metabolic switch during B cell activation (Caro-Maldonado et al, 2014;Le et al, 2012). How these two key metabolic nutrients are regulated in a synchronized manner to maintain defined levels of the building blocks and energy needed for antibody production remained unclear, and our studies indicate a critical modulating role of the let7adf cluster in this process.…”

“…Emerging evidence indicates that upon antigen encounter, B cells reprogram metabolism to meet the biosynthetic demands for antibody production (Capasso et al, 2015;Caro-Maldonado et al, 2014;Doughty et al, 2006;Le et al, 2012). Activation of B cells is accompanied by increased glycolysis and glutaminolysis (Buck et al, 2015;Caro-Maldonado et al, 2014;Dufort et al, 2007;Woodland et al, 2008).…”

“…As the most abundant amino acid in serum, glutamine is a readily available nutrient for most cells, and is involved in providing nitrogen for synthesis of many amino acids (Caro-Maldonado et al, 2014;Hensley et al, 2013). Several genes associated with amino acid transport and biosynthesis are induced under starvation conditions in various cell types, including B cells (Le et al, 2012;Shotwell et al, 1983). However, despite the fundamental role of necessary nutrients-glucose and glutamine-as building blocks for protein synthesis and substrates for multiple metabolic processes, regulation of uptake and utilization of these two key nutrients during B cell activation is incompletely understood.…”

Glutamine at focus: versatile roles in cancer

“…Other reports using another specific GLS1 inhibitor (BPTES) showed great efficacy to slow growth of glioblastoma-associated IDH1 mutant, as well as inhibited the proliferation of many glutamine-addicted cancer cell types Tumor Biol. [13,152,153]. In addition, other reports have revealed the effect of innumerous glutamine metabolism inhibitors.…”

Metabolic Signature Genes Associated with Susceptibility to Pyruvate Kinase, Muscle Type 2 Gene Ablation in Cancer Cells

“…In some cancer cells, glutamine is a major source for replenishing the intermediates of the TCA cycle required by the continual loss of citrate and malate (another source of acetyl-CoA) from the cycle. Therefore, glutamine uptake and oxidation are important factors for the bioenergetics and biomaterial supplies in cancer cells (Le et al, 2012;Wise and Thompson, 2010). Myc stimulates glutamine metabolism by inducing the expression of glutamine metabolism genes, such as the glutamine transporter SLC1A5 and carbamoyl phosphate synthetase II (CAD) genes (Bush et al, 1998;Wise et al, 2008), or by suppressing the expression of the glutaminase (GLS)-targeting miR-23a/b gene (Gao et al, 2009).…”