Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B-cells

By A. Le, Andrew N. Lane, M. Hamaker, S. Bose, A. Gouw, J. Barbi, T. Tsukamoto, C. J. Rojas, B. Slusher, Haixia Zhang and 7 more. Cell Metabolism, 2012

1,071 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/0d7ca3facb87e69173734f3d3857e032f8d63548

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Ralph J. Deberardinis
2. M. V. Vander Heiden
3. C. V. Dang
4. Craig B. Thompson
5. Huafeng Zhang
6. Erika L. Pearce
7. Russell G. Jones
8. Patrick S. Ward

In Molecular Biology

1. Ralph J. Deberardinis
2. M. V. Vander Heiden
3. Craig B. Thompson
4. C. V. Dang
5. Huafeng Zhang
6. Erika L. Pearce
7. Zhaoyong Li
8. Russell G. Jones

Citations in the corpus

• Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013, background): “Glutamine transporters (SNAT1 and SNAT2) as well as key glutaminolysis enzymes (GLS, GPT, GOT, and GLUD) are upregulated early after T cell activation similar to glycolysis genes (7, 9); several groups have correlated these changes in gene expression to enhanced glutaminolytic flux in lymphocytes (9”
• Memory CD8+ T cells use cell intrinsic lipolysis to support the metabolic programming necessary for development (2014, background): “In cancer cells, glutamine provides an alternate carbon source for lipid synthesis in LG (Le et al., 2012); however, we found that excess glutamine did not rescue the defects in IL-15 memory T cell metabolism (Figure S2F).”
• Metabolic Reprogramming: A Cancer Hallmark Even Warburg Did Not Anticipate (2012, background): “Either siRNA knockdown or pharmacological inhibition of GLS can inhibit Rho-GTPase-induced transformation and proliferation (Wang et al., 2010).”
• MYC, Metabolism, and Cancer. (2015, background): “Pharmacologic inhibition of GLS has also been documented to curb tumor progression of an inducible MYC-driven human lymphoma xenograft model in a cellautonomous fashion (212, 213).”
• Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression (2015, background): “found that cMyc induces glutamine to glutamate conversion that persists in hypoxia, and glutamine contributed significantly to citrate carbons [116].”
• MYC, metabolism, cell growth, and tumorigenesis. (2013, background): “In fact, the growing B cell uses a TCA cycle comprised of hybrid intermediates containing carbons from both glucose and glutamine to generate carbon skeletons for macromolecular synthesis (DeBerardinis and Cheng 2010; Le et al. 2012).”
• Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches (2019, background): “c-MYC is one of the main regulators of glutaminolysis and is also overexpressed in the vast majority of tumors (58).”
• Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport (2014, background): “A similar pathway to the one described here was identified in c-Myc-expressing lymphoma cells under glucose deprivation (Le et al., 2012).”
• MYC on the Path to Cancer (2012, background): “…such as ornithine decarboxylase (ODC), lactate dehydrogenase A (LDHA), and glutaminase (GLS) have also been targeted by shRNAs or drug-like small molecules in vivo (Figure 3) (Fantin et al., 2006; Le et al., 2010, 2012; Seltzer et al., 2010; Seth et al., 2011; Wang et al., 2010; Xie et al., 2009).”
• c-Myc and Cancer Metabolism (2012, positive): “Recent studies have shown that cancer-related alterations in glucose and glutamine metabolism are strongly influenced by c-Myc expression (79).”