A Non-Canonical Convergence of Carbohydrate and Glutamine Metabolism is Required After Metabolic Rewiring in a Solid Environment

The fate of pyruvate, which is modulated mitochondrial pyruvate carrier (MPC) activity, is a defining metabolic feature in many cancers. Diffuse large B-cell lymphomas (DLBCLs) are a genetically and metabolically heterogenous cancer. Although MPC expression and activity differed between DLBCL subgroups, mitochondrial pyruvate oxidation was uniformly minimal. Mitochondrial pyruvate was instead robustly consumed by glutamate pyruvate transaminase 2 to support α-ketoglutarate production as part of glutamine catabolism. This led us to discover that glutamine exceeds pyruvate as a carbon source for the TCA cycle, but, MPC function is required to enable GPT2-mediated glutamine catabolism. Furthermore, we found that MPC inhibition only decreased DLBCL proliferation in a solid culture environment, but not in a suspension environment. Thus, the non-canonical connection between the consumption and assimilation of carbohydrates and glutamine in DLBCLs enables their proliferation in a solid 3D environment.Mitochondrial pyruvate supports glutaminolysis in DLBCLs by supplying pyruvate for GPT2-mediated α-KG production.Glutamine, but not glucose, is a major carbon source for the TCA cycle in DLBCLs.Citrate is minimally oxidized in the TCA cycle in DLBCLs.α-KG production is important for DLBCLs proliferation in a 3D ECM environment.The mitochondrial pyruvate carrier supports DLBCL proliferation in a 3D ECM environment.

[1]  K. Parnell,et al.  The pyruvate-lactate axis modulates cardiac hypertrophy and heart failure. , 2020, Cell metabolism.

[2]  P. Georgel,et al.  Genetic and epigenetic determinants of diffuse large B-cell lymphoma , 2020, Blood Cancer Journal.

[3]  D. Ribatti,et al.  New Insights into Diffuse Large B-Cell Lymphoma Pathobiology , 2020, Cancers.

[4]  Sara M. Nowinski,et al.  Regulation of Tumor Initiation by the Mitochondrial Pyruvate Carrier. , 2019, Cell metabolism.

[5]  E. Taylor,et al.  Disrupting Mitochondrial Pyruvate Uptake Directs Glutamine into the TCA Cycle away from Glutathione Synthesis and Impairs Hepatocellular Tumorigenesis , 2019, Cell reports.

[6]  B. Nadel,et al.  GAPDH Expression Predicts the Response to R-CHOP, the Tumor Metabolic Status, and the Response of DLBCL Patients to Metabolic Inhibitors. , 2019, Cell metabolism.

[7]  C. Verfaillie,et al.  Breast cancer cells rely on environmental pyruvate to shape the metastatic niche , 2019, Nature.

[8]  W. Cui,et al.  MPC1 deficiency accelerates lung adenocarcinoma progression through the STAT3 pathway , 2019, Cell Death & Disease.

[9]  B. Garcia,et al.  Acetyl-CoA Metabolism Supports Multistep Pancreatic Tumorigenesis. , 2019, Cancer discovery.

[10]  Eric A. Smith,et al.  Mitochondrial pyruvate import is a metabolic vulnerability in androgen receptor-driven prostate cancer , 2018, Nature Metabolism.

[11]  L. Staudt,et al.  Mechanisms of Disease , 2010 .

[12]  X. Bian,et al.  Mitochondrial pyruvate carrier 1 functions as a tumor suppressor and predicts the prognosis of human renal cell carcinoma , 2018, Laboratory Investigation.

[13]  S. Sivanand,et al.  Spatiotemporal Control of Acetyl-CoA Metabolism in Chromatin Regulation. , 2018, Trends in biochemical sciences.

[14]  Sarah Jeanfavre,et al.  Metabolic recycling of ammonia via glutamate dehydrogenase supports breast cancer biomass , 2017, Science.

[15]  Jamey D. Young,et al.  Lactate Metabolism in Human Lung Tumors , 2017, Cell.

[16]  Benjamin P. C. Chen,et al.  CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells , 2017, Nature.

[17]  M. Shipp,et al.  Differential contribution of the mitochondrial translation pathway to the survival of diffuse large B-cell lymphoma subsets , 2016, Cell Death and Differentiation.

[18]  J. Nesland,et al.  Mitochondrial pyruvate carrier function is negatively linked to Warburg phenotype in vitro and malignant features in esophageal squamous cell carcinomas , 2016, Oncotarget.

[19]  Christian M. Metallo,et al.  Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death , 2017, The Journal of cell biology.

[20]  Christian M. Metallo,et al.  Reductive carboxylation supports redox homeostasis during anchorage-independent growth , 2016, Nature.

[21]  I. Grosse,et al.  Normoxic accumulation of HIF1α is associated with glutaminolysis , 2016, Clinical Oral Investigations.

[22]  Matthew E. Ritchie,et al.  limma powers differential expression analyses for RNA-sequencing and microarray studies , 2015, Nucleic acids research.

[23]  H. Kleinman,et al.  Matrigel: from discovery and ECM mimicry to assays and models for cancer research. , 2014, Advanced drug delivery reviews.

[24]  Jianxin Xie,et al.  A role for the mitochondrial pyruvate carrier as a repressor of the Warburg effect and colon cancer cell growth. , 2014, Molecular cell.

[25]  R. Deberardinis,et al.  Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport. , 2014, Molecular cell.

[26]  Jennifer B Dennison,et al.  Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer , 2014, Molecular Cancer Therapeutics.

[27]  J. Rutter.  Mitochondrial pyruvate carrier , 2014 .

[28]  Thomas M. Wasylenko,et al.  Reductive glutamine metabolism is a function of the α-ketoglutarate to citrate ratio in cells , 2013, Nature Communications.

[29]  Michael R. Green,et al.  Metabolic signatures uncover distinct targets in molecular subsets of diffuse large B cell lymphoma. , 2012, Cancer cell.

[30]  Claire Redin,et al.  A Mitochondrial Pyruvate Carrier Required for Pyruvate Uptake in Yeast, Drosophila, and Humans , 2012, Science.

[31]  Christian M. Metallo,et al.  Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia , 2011, Nature.

[32]  W. Marston Linehan,et al.  Reductive carboxylation supports growth in tumor cells with defective mitochondria , 2011, Nature.

[33]  A. Plaitakis,et al.  The Role of Glutamate Dehydrogenase in Mammalian Ammonia Metabolism , 2011, Neurotoxicity research.

[34]  L. Staudt,et al.  High microvessel density determines a poor outcome in patients with diffuse large B-cell lymphoma treated with rituximab plus chemotherapy , 2011, Haematologica.

[35]  Judy Lucas,et al.  Ammonia Derived from Glutaminolysis Is a Diffusible Regulator of Autophagy , 2010, Science Signaling.

[36]  Hadley Wickham,et al.  ggplot2 - Elegant Graphics for Data Analysis (2nd Edition) , 2017 .

[37]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[38]  J. Leonard,et al.  Targeting angiogenesis: a novel, rational therapeutic approach for non-Hodgkin lymphoma , 2009, Leukemia & lymphoma.

[39]  A C C Gibbs,et al.  Data Analysis , 2009, Encyclopedia of Database Systems.

[40]  Debra L Winkeljohn.  Triple-negative breast cancer. , 2008, Clinical journal of oncology nursing.

[41]  Sean R. Davis,et al.  GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor , 2007, Bioinform..

[42]  M. Shipp,et al.  Advances in the biology and therapy of diffuse large B-cell lymphoma: moving toward a molecularly targeted approach. , 2005, Blood.

[43]  T. Golub,et al.  Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. , 2004, Blood.

[44]  K. Gatter,et al.  Vascular patterns in reactive lymphoid tissue and in non-Hodgkin's lymphoma , 2003, British Journal of Cancer.

[45]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.