scholarly journals SIRT5 stabilizes mitochondrial glutaminase and supports breast cancer tumorigenesis

2019 ◽  
Vol 116 (52) ◽  
pp. 26625-26632 ◽  
Author(s):  
Kai Su Greene ◽  
Michael J. Lukey ◽  
Xueying Wang ◽  
Bryant Blank ◽  
Joseph E. Druso ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Mammary Tumorigenesis ◽  
Cellular Transformation ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Mitochondrial Enzyme ◽  
Human Breast ◽  
Poor Patient ◽  
Patient Prognosis ◽  
Hydrolysis Of

The mitochondrial enzyme glutaminase (GLS) is frequently up-regulated during tumorigenesis and is being evaluated as a target for cancer therapy. GLS catalyzes the hydrolysis of glutamine to glutamate, which then supplies diverse metabolic pathways with carbon and/or nitrogen. Here, we report that SIRT5, a mitochondrial NAD+-dependent lysine deacylase, plays a key role in stabilizing GLS. In transformed cells, SIRT5 regulates glutamine metabolism by desuccinylating GLS and thereby protecting it from ubiquitin-mediated degradation. Moreover, we show that SIRT5 is up-regulated during cellular transformation and supports proliferation and tumorigenesis. Elevated SIRT5 expression in human breast tumors correlates with poor patient prognosis. These findings reveal a mechanism for increasing GLS expression in cancer cells and establish a role for SIRT5 in metabolic reprogramming and mammary tumorigenesis.

scholarly journals Spatially resolved metabolomics to discover tumor-associated metabolic alterations

2018 ◽  
Vol 116 (1) ◽  
pp. 52-57 ◽  
Author(s):  
Chenglong Sun ◽  
Tiegang Li ◽  
Xiaowei Song ◽  
Luojiao Huang ◽  
Qingce Zang ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Fatty Acid Biosynthesis ◽  
Spatial Information ◽  
Tumor Therapy ◽  
Metabolic Enzymes ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Ionization Mass ◽  
Metabolic Alterations ◽  
Spatially Resolved

Characterization of tumor metabolism with spatial information contributes to our understanding of complex cancer metabolic reprogramming, facilitating the discovery of potential metabolic vulnerabilities that might be targeted for tumor therapy. However, given the metabolic variability and flexibility of tumors, it is still challenging to characterize global metabolic alterations in heterogeneous cancer. Here, we propose a spatially resolved metabolomics approach to discover tumor-associated metabolites and metabolic enzymes directly in their native state. A variety of metabolites localized in different metabolic pathways were mapped by airflow-assisted desorption electrospray ionization mass spectrometry imaging (AFADESI-MSI) in tissues from 256 esophageal cancer patients. In combination with in situ metabolomics analysis, this method provided clues into tumor-associated metabolic pathways, including proline biosynthesis, glutamine metabolism, uridine metabolism, histidine metabolism, fatty acid biosynthesis, and polyamine biosynthesis. Six abnormally expressed metabolic enzymes that are closely associated with the altered metabolic pathways were further discovered in esophageal squamous cell carcinoma (ESCC). Notably, pyrroline-5-carboxylate reductase 2 (PYCR2) and uridine phosphorylase 1 (UPase1) were found to be altered in ESCC. The spatially resolved metabolomics reveal what occurs in cancer at the molecular level, from metabolites to enzymes, and thus provide insights into the understanding of cancer metabolic reprogramming.

scholarly journals Metabolic reprogramming and metabolic sensors in KSHV-induced cancers and KSHV infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tingting Li ◽  
Shou-Jiang Gao
Keyword(s):  
Cell Proliferation ◽  
Metabolic Pathways ◽  
Molecular Basis ◽  
Building Blocks ◽  
Cellular Transformation ◽  
Metabolic Reprogramming ◽  
Kshv Infection ◽  
New Therapies ◽  
Human Cancers ◽  
Infected Cells

AbstractKaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic gammaherpesvirus associated with several human cancers. KSHV infection and KSHV-induced anabolic cell proliferation and cellular transformation depend on reprogramming of cellular metabolic pathways, which provide the building blocks and energy for the growth of both the virus and the infected cells. Furthermore, KSHV dysregulates numerous metabolic sensors including mTOR, AMPK, CASTOR1 and sirtuins to maintain cellular energetic homeostasis during infection and in KSHV-induced cancers. In this review, we summarize the recent advances in the understanding of KSHV hijacking of metabolic pathways and sensors, providing insights into the molecular basis of KSHV infection and KSHV-induced oncogenesis. In addition, we highlight the critical metabolic targets and sensors for developing potential new therapies against KSHV infection and KSHV-induced cancers.

Metabolic Reprogramming of Cancer by Chemicals that Target Glutaminase Isoenzymes

2020 ◽  
Vol 27 (32) ◽  
pp. 5317-5339 ◽  
Author(s):  
José M. Matés ◽  
José A. Campos-Sandoval ◽  
Juan de los Santos-Jiménez ◽  
Juan A. Segura ◽  
Francisco J. Alonso ◽  
...  
Keyword(s):  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Expression Patterns ◽  
Therapeutic Agents ◽  
Tumour Suppressor ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Tumour Suppressor Genes ◽  
Suppressor Factor ◽  
Functional Roles

Background: Metabolic reprogramming of tumours is a hallmark of cancer. Among the changes in the metabolic network of cancer cells, glutaminolysis is a key reaction altered in neoplasms. Glutaminase proteins control the first step in glutamine metabolism and their expression correlates with malignancy and growth rate of a great variety of cancers. The two types of glutaminase isoenzymes, GLS and GLS2, differ in their expression patterns and functional roles: GLS has oncogenic properties and GLS2 has been described as a tumour suppressor factor. Results: We have focused on glutaminase connections with key oncogenes and tumour suppressor genes. Targeting glutaminase isoenzymes includes different strategies aimed at deactivating the rewiring of cancer metabolism. In addition, we found a long list of metabolic enzymes, transcription factors and signalling pathways dealing with glutaminase. On the other hand, a number of chemicals have been described as isoenzyme-specific inhibitors of GLS and/or GLS2 isoforms. These molecules are being characterized as synergic and therapeutic agents in many types of tumours. Conclusion: This review states the metabolic pathways that are rewired in cancer, the roles of glutaminase isoforms in cancer, as well as the metabolic circuits regulated by glutaminases. We also show the plethora of anticancer drugs that specifically inhibit glutaminase isoenzymes for treating several sets of cancer.

scholarly journals Mammary Tumorigenesis and Metastasis Caused by Overexpression of Insulin Receptor Substrate 1 (IRS-1) or IRS-2

2006 ◽  
Vol 26 (24) ◽  
pp. 9302-9314 ◽  
Author(s):  
Robert K. Dearth ◽  
Xiaojiang Cui ◽  
Hyun-Jung Kim ◽  
Isere Kuiatse ◽  
Nicole A. Lawrence ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Kinase Activity ◽  
Mammary Tumorigenesis ◽  
Poor Patient ◽  
Insulin Receptor Substrates ◽  
Mammary Hyperplasia ◽  
Patient Prognosis ◽  
Insulin Like Growth Factors

ABSTRACT Insulin receptor substrates (IRSs) are signaling adaptors that play a major role in the metabolic and mitogenic actions of insulin and insulin-like growth factors. Reports have recently noted increased levels, or activity, of IRSs in many human cancers, and some have linked this to poor patient prognosis. We found that overexpressed IRS-1 was constitutively phosphorylated in vitro and in vivo and that transgenic mice overexpressing IRS-1 or IRS-2 in the mammary gland showed progressive mammary hyperplasia, tumorigenesis, and metastasis. Tumors showed extensive squamous differentiation, a phenotype commonly seen with activation of the canonical β-catenin signaling pathway. Consistent with this, IRSs were found to bind β-catenin in vitro and in vivo. IRS-induced tumorigenesis is unique, given that the IRSs are signaling adaptors with no intrinsic kinase activity, and this supports a growing literature indicating a role for IRSs in cancer. This study defines IRSs as oncogene proteins in vivo and provides new models to develop inhibitors against IRSs for anticancer therapy.

scholarly journals Phytochemicals Block Glucose Utilization and Lipid Synthesis to Counteract Metabolic Reprogramming in Cancer Cells

2021 ◽  
Vol 11 (3) ◽  
pp. 1259
Author(s):  
Qiong Wu ◽  
Bo Zhao ◽  
Guangchao Sui ◽  
Jinming Shi
Keyword(s):  
Cancer Cells ◽  
Metabolic Pathways ◽  
De Novo ◽  
Aerobic Glycolysis ◽  
Structural Characteristics ◽  
Natural Compounds ◽  
Metabolic Reprogramming ◽  
De Novo Lipogenesis ◽  
Anticancer Activities ◽  
Substrate Analogs

Aberrant metabolism is one of the hallmarks of cancers. The contributions of dysregulated metabolism to cancer development, such as tumor cell survival, metastasis and drug resistance, have been extensively characterized. “Reprogrammed” metabolic pathways in cancer cells are mainly represented by excessive glucose consumption and hyperactive de novo lipogenesis. Natural compounds with anticancer activities are constantly being demonstrated to target metabolic processes, such as glucose transport, aerobic glycolysis, fatty acid synthesis and desaturation. However, their molecular targets and underlying anticancer mechanisms remain largely unclear or controversial. Mounting evidence indicated that these natural compounds could modulate the expression of key regulatory enzymes in various metabolic pathways at transcriptional and translational levels. Meanwhile, natural compounds could also inhibit the activities of these enzymes by acting as substrate analogs or altering their protein conformations. The actions of natural compounds in the crosstalk between metabolism modulation and cancer cell destiny have become increasingly attractive. In this review, we summarize the activities of natural small molecules in inhibiting key enzymes of metabolic pathways. We illustrate the structural characteristics of these compounds at the molecular level as either inhibitor of various enzymes or regulators of metabolic pathways in cancer cells. Our ultimate goal is to both facilitate the clinical application of natural compounds in cancer therapies and promote the development of novel anticancer therapeutics.

scholarly journals Role of dendritic cell metabolic reprogramming in tumor immune evasion

2020 ◽  
Vol 32 (7) ◽  
pp. 485-491 ◽  
Author(s):  
Michael P Plebanek ◽  
Michael Sturdivant ◽  
Nicholas C DeVito ◽  
Brent A Hanks
Keyword(s):  
Dendritic Cell ◽  
Metabolic Pathways ◽  
Checkpoint Inhibitor ◽  
Therapeutic Strategies ◽  
Metabolic Reprogramming ◽  
Combination Immunotherapy ◽  
Tumor Immune Evasion ◽  
Effector T Cell ◽  
Cell Responses

Abstract The dendritic cell (DC) is recognized as a vital mediator of anti-tumor immunity. More recent studies have also demonstrated the important role of DCs in the generation of effective responses to checkpoint inhibitor immunotherapy. Metabolic programming of DCs dictates their functionality and can determine which DCs become immunostimulatory versus those that develop a tolerized phenotype capable of actively suppressing effector T-cell responses to cancers. As a result, there is great interest in understanding what mechanisms have evolved in cancers to alter these metabolic pathways, thereby allowing for their continued progression and metastasis. The therapeutic strategies developed to reverse these processes of DC tolerization in the tumor microenvironment represent promising candidates for future testing in combination immunotherapy clinical trials.

Glutamine anaplerosis is required for amino acid biosynthesis in human meningiomas

2021 ◽  
Author(s):  
Omkar B Ijare ◽  
Shashank Hambarde ◽  
Fabio Henrique Brasil da Costa ◽  
Sophie Lopez ◽  
Martyn A Sharpe ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Acid Biosynthesis ◽  
Tumor Tissues ◽  
Metabolite Profiles ◽  
Human Meningiomas ◽  
Grade Ii ◽  
Nonessential Amino Acids ◽  
Tracer Experiments

Abstract Background We postulate that meningiomas undergo distinct metabolic reprogramming in tumorigenesis and unravelling their metabolic phenotypes provide new therapeutic insights. Glutamine catabolism is key to the growth and proliferation of tumors. Here, we investigated the metabolomics of freshly resected meningiomas and glutamine metabolism in patient-derived meningioma cells. Methods 1H NMR spectroscopy of tumor tissues from 33 meningioma patients was used to differentiate the metabolite profiles of grade-I and grade-II meningiomas. Glutamine metabolism was examined using 13C/ 15N glutamine tracer, in five patient-derived meningioma cells. Results Alanine, lactate, glutamate, glutamine, and glycine were predominantly elevated only in grade-II meningiomas by 74%, 76%, 35%, 75% and 33% respectively, with alanine, and glutamine being statistically significant (p ≤ 0.02). 13C/ 15N glutamine tracer experiments revealed that both grade-I and -II meningiomas actively metabolize glutamine to generate various key carbon intermediates including alanine and proline that are necessary for the tumor growth. Also, it is shown that glutaminase (GLS1) inhibitor, CB-839 is highly effective in downregulating glutamine metabolism and decreasing proliferation in meningioma cells. Conclusion Alanine and glutamine/glutamate are mainly elevated in grade-II meningiomas. Grade-I meningiomas possess relatively higher glutamine metabolism providing carbon/nitrogen for the biosynthesis of key nonessential amino acids. GLS1 inhibitor (CB-839) would be very effective in downregulating glutamine metabolic pathways in grade-I meningiomas leading to decreased cellular proliferation.

SARS-Coronavirus 2, A Metabolic Reprogrammer: A Review in the Context of the Possible Therapeutic Strategies

2021 ◽  
Vol 22 ◽  
Author(s):  
Poornima Gopi ◽  
TR Anju ◽  
Vinod Soman Pillai ◽  
Mohanan Veettil
Keyword(s):  
Virus Infection ◽  
Host Cell ◽  
Metabolic Pathways ◽  
Inflammatory Responses ◽  
Membrane Lipid ◽  
Therapeutic Strategies ◽  
Metabolic Reprogramming ◽  
Multiple Organs ◽  
The Cross ◽  
The Impact

: Novel coronavirus, SARS-CoV-2 is advancing at a staggering pace to devastate the health care system and foster the concerns over public health. In contrast to the past outbreaks, coronaviruses aren’t clinging themselves as a strict respiratory virus. Rather, becoming a multifaceted virus, it affects multiple organs by interrupting a number of metabolic pathways leading to significant rates of morbidity and mortality. Following infection they rigorously reprogram multiple metabolic pathways of glucose, lipid, protein, nucleic acid and their metabolites to extract adequate energy and carbon skeletons required for their existence and further molecular constructions inside a host cell. Although the mechanism of these alterations are yet to be known, the impact of these reprogramming is reflected in the hyper inflammatory responses, so called cytokine storm and the hindrance of host immune defence system. The metabolic reprogramming during SARS-CoV-2 infection needs to be considered while devising therapeutic strategies to combat the disease and its further complication. The inhibitors of cholesterol and phospholipids synthesis and cell membrane lipid raft of the host cell can, to a great extent, control the viral load and further infection. Depletion of energy source by inhibiting the activation of glycolytic and hexoseamine biosynthetic pathway can also augment the antiviral therapy. The cross talk between these pathways also necessitates the inhibition of amino acid catabolism and tryptophan metabolism. A combinatorial strategy which can address the cross talks between the metabolic pathways might be more effective than a single approach and the infection stage and timing of therapy will also influence the effectiveness of the antiviral approach. We herein focus on the different metabolic alterations during the course of virus infection that help to exploit the cellular machinery and devise a therapeutic strategy which promotes resistance to viral infection and can augment body’s antivirulence mechanisms. This review may cast the light into the possibilities of targeting altered metabolic pathways to defend virus infection in a new perspective.

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