glutaminase and Cell-Transformation--Neoplastic

The metabolic adaptations that support oncogenic growth can also render cancer cells dependent on certain nutrients. Along with the Warburg effect, increased utilization of glutamine is one of the metabolic hallmarks of the transformed state. Glutamine catabolism is positively regulated by multiple oncogenic signals, including those transmitted by the Rho family of GTPases and by c-Myc. The recent identification of mechanistically distinct inhibitors of glutaminase, which can selectively block cellular transformation, has revived interest in the possibility of targeting glutamine metabolism in cancer therapy. Here, we outline the regulation and roles of glutamine metabolism within cancer cells and discuss possible strategies for, and the consequences of, impacting these processes therapeutically.

Topics: Animals; Antineoplastic Agents; Cell Transformation, Neoplastic; Glutaminase; Glutamine; Humans; Models, Molecular; Molecular Targeted Therapy; Neoplasms; Signal Transduction

Over 80 years ago, Warburg discovered that cancer cells generate ATP through the glycolytic pathway, even in the presence of oxygen. The finding of this phenomenon, termed the "Warburg effect," stimulated much research on tumorigenesis, but few explanations were forthcoming to explain the observation. Recently, advanced developments in molecular biology and high-throughput molecular analyses have revealed that many of the signaling pathways altered by gene mutations regulate cell metabolism in cancer. Furthermore, mutations in isocitrate dehydrogenase 1 and 2 were shown to elevate 2-hydroxyglutarate, which led to changes in α-ketoglutarate-dependent dioxygenase enzyme activity, resulting in an increased risk of malignant tumors. Although these findings led to a renewed interest in cancer metabolism, our knowledge on the specifics of tumor metabolism is still fragmented. This paper reviews recent findings related to key transcription factors and enzymes that play an important role in the regulation of cancer metabolism.

Topics: Basic Helix-Loop-Helix Transcription Factors; Cell Transformation, Neoplastic; Fumarates; Genes, p53; Glutaminase; Glycolysis; Humans; Isocitrate Dehydrogenase; Mutation; Neoplasms; Proto-Oncogene Proteins c-myc; Pyruvate Kinase

Cellular energy metabolism is one of the main processes affected during the transition from normal to cancer cells, and it is a crucial determinant of cell proliferation or cell death. As a support for rapid proliferation, cancer cells choose to use glycolysis even in the presence of oxygen (Warburg effect) to fuel macromolecules for the synthesis of nucleotides, fatty acids, and amino acids for the accelerated mitosis, rather than fuel the tricarboxylic acid cycle and oxidative phosphorylation. Mitochondria biogenesis is also reprogrammed in cancer cells, and the destiny of those cells is determined by the balance between energy and macromolecule supplies, and the efficiency of buffering of the cumulative radical oxygen species. In glioblastoma, the most frequent and malignant adult brain tumor, a metabolic shift toward aerobic glycolysis is observed, with regulation by well known genes as integrants of oncogenic pathways such as phosphoinositide 3-kinase/protein kinase, MYC, and hypoxia regulated gene as hypoxia induced factor 1. The expression profile of a set of genes coding for glycolysis and the tricarboxylic acid cycle in glioblastoma cases confirms this metabolic switch. An understanding of how the main metabolic pathways are modified by cancer cells and the interactions between oncogenes and tumor suppressor genes with these pathways may enlighten new strategies in cancer therapy. In the present review, the main metabolic pathways are compared in normal and cancer cells, and key regulations by the main oncogenes and tumor suppressor genes are discussed. Potential therapeutic targets of the cancer energetic metabolism are enumerated, highlighting the astrocytomas, the most common brain cancer.

Topics: Brain Neoplasms; Cell Proliferation; Cell Transformation, Neoplastic; Citric Acid Cycle; Glutaminase; Glutamine; Glycolysis; Humans; Oncogenes; Pentose Phosphate Pathway; Stem Cells

Cancer cells re-program their metabolic machinery in order to satisfy their bioenergetic and biosynthetic requirements. A critical aspect of the re-programming of cancer cell metabolism involves changes in the glycolytic pathway (referred to as the "Warburg effect"). As an outcome of these changes, much of the pyruvate generated via the glycolytic pathway is converted to lactic acid, rather than being used to produce acetyl-CoA and ultimately, the citrate which enters the citric acid cycle. In order to compensate for these changes and to help maintain a functioning citric acid cycle, cancer cells often rely on elevated glutamine metabolism. Recently, we have found that this is achieved through a marked elevation of glutaminase activity in cancer cells. Here we further consider these findings and the possible mechanisms by which this important metabolic activity is regulated.

Topics: Animals; Cell Transformation, Neoplastic; Energy Metabolism; Enzyme Inhibitors; Glutaminase; Humans; Metabolic Networks and Pathways; Models, Biological; Neoplasms; rho GTP-Binding Proteins

Topics: Animals; Aspartate Aminotransferases; Carbamates; Cell Transformation, Neoplastic; DNA Nucleotidyltransferases; Fructose-Bisphosphatase; Fructose-Bisphosphate Aldolase; Fructosephosphates; Glutaminase; Glycerolphosphate Dehydrogenase; Hexokinase; Isocitrate Dehydrogenase; Isoenzymes; Kinetics; L-Lactate Dehydrogenase; Malate Dehydrogenase; Molecular Weight; NAD; NADP; Neoplasms; Phosphotransferases; Pyruvate Kinase; Transferases

Inhibiting cancer metabolism via glutaminase (GAC) is a promising strategy to disrupt tumor progression. However, mechanism regarding GAC acetylation remains mostly unknown. In this study, we demonstrate that lysine acetylation is a vital post-translational modification that inhibits GAC activity in non-small cell lung cancer (NSCLC). We identify that Lys311 is the key acetylation site on GAC, which is deacetylated by HDAC4, a class II deacetylase. Lys311 acetylation stimulates the interaction between GAC and TRIM21, an E3 ubiquitin ligase of the tripartite motif (TRIM) family, therefore promoting GAC K63-linked ubiquitination and inhibiting GAC activity. Furthermore, GAC

Topics: Acetylation; Carcinogenesis; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Cell Transformation, Neoplastic; Glutaminase; Histone Deacetylases; Humans; Lung Neoplasms; Repressor Proteins; Ubiquitination

Many transformed cells exhibit altered glucose metabolism and increased utilization of glutamine for anabolic and bioenergetic processes. These metabolic adaptations, which accompany tumorigenesis, are driven by oncogenic signals. Here we report that the transcription factor c-Jun, product of the proto-oncogene JUN, is a key regulator of mitochondrial glutaminase (GLS) levels. Activation of c-Jun downstream of oncogenic Rho GTPase signalling leads to elevated GLS gene expression and glutaminase activity. In human breast cancer cells, GLS protein levels and sensitivity to GLS inhibition correlate strongly with c-Jun levels. We show that c-Jun directly binds to the GLS promoter region, and is sufficient to increase gene expression. Furthermore, ectopic overexpression of c-Jun renders breast cancer cells dependent on GLS activity. These findings reveal a role for c-Jun as a driver of cancer cell metabolic reprogramming, and suggest that cancers overexpressing JUN may be especially sensitive to GLS-targeted therapies.

Topics: Animals; Base Sequence; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Embryo, Mammalian; Fibroblasts; Gene Expression Regulation, Neoplastic; Glutaminase; Glutamine; Humans; MCF-7 Cells; Mice; Molecular Sequence Data; Neoplasms; Promoter Regions, Genetic; Protein Binding; Proto-Oncogene Mas; Proto-Oncogene Proteins c-jun; Reverse Transcriptase Polymerase Chain Reaction; rho GTP-Binding Proteins; RNA Interference

Glutaminase (GLS), which converts glutamine to glutamate, plays a key role in cancer cell metabolism, growth, and proliferation. GLS is being explored as a cancer therapeutic target, but whether GLS inhibitors affect cancer cell-autonomous growth or the host microenvironment or have off-target effects is unknown. Here, we report that loss of one copy of Gls blunted tumor progression in an immune-competent MYC-mediated mouse model of hepatocellular carcinoma. Compared with results in untreated animals with MYC-induced hepatocellular carcinoma, administration of the GLS-specific inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) prolonged survival without any apparent toxicities. BPTES also inhibited growth of a MYC-dependent human B cell lymphoma cell line (P493) by blocking DNA replication, leading to cell death and fragmentation. In mice harboring P493 tumor xenografts, BPTES treatment inhibited tumor cell growth; however, P493 xenografts expressing a BPTES-resistant GLS mutant (GLS-K325A) or overexpressing GLS were not affected by BPTES treatment. Moreover, a customized Vivo-Morpholino that targets human GLS mRNA markedly inhibited P493 xenograft growth without affecting mouse Gls expression. Conversely, a Vivo-Morpholino directed at mouse Gls had no antitumor activity in vivo. Collectively, our studies demonstrate that GLS is required for tumorigenesis and support small molecule and genetic inhibition of GLS as potential approaches for targeting the tumor cell-autonomous dependence on GLS for cancer therapy.

Topics: Amino Acid Substitution; Animals; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Glutaminase; Heterografts; Humans; Liver Neoplasms, Experimental; Mice; Mice, Inbred BALB C; Mice, Transgenic; Mutation, Missense; Neoplasm Transplantation; Sulfides; Thiadiazoles

Rho GTPases impact a number of activities important for oncogenesis. We describe a small molecule inhibitor that blocks oncogenic transformation induced by various Rho GTPases in fibroblasts, and the growth of human breast cancer and B lymphoma cells, without affecting normal cells. We identify the target of this inhibitor to be the metabolic enzyme glutaminase, which catalyzes the hydrolysis of glutamine to glutamate. We show that transformed fibroblasts and breast cancer cells exhibit elevated glutaminase activity that is dependent on Rho GTPases and NF-κB activity, and is blocked by the small molecule inhibitor. These findings highlight a previously unappreciated connection between Rho GTPase activation and cellular metabolism and demonstrate that targeting glutaminase activity can inhibit oncogenic transformation.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Transformation, Neoplastic; Enzyme Inhibitors; Female; Fibroblasts; Glutaminase; Humans; Mice; Mitochondria; NIH 3T3 Cells; rho GTP-Binding Proteins; Signal Transduction; Transfection