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 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 Targeting Cancer Metabolism to Resensitize Chemotherapy: Potential Development of Cancer Chemosensitizers from Traditional Chinese Medicines

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 404 ◽  
Author(s):  
Guo ◽  
Tan ◽  
Chen ◽  
Wang ◽  
Feng
Keyword(s):  
Chinese Medicine ◽  
Cancer Therapy ◽  
Traditional Chinese Medicine ◽  
Cancer Cells ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Metabolic Reprogramming ◽  
Traditional Chinese Medicines ◽  
Chinese Medicines ◽  
Incidence And Mortality

Cancer is a common and complex disease with high incidence and mortality rates, which causes a severe public health problem worldwide. As one of the standard therapeutic approaches for cancer therapy, the prognosis and outcome of chemotherapy are still far from satisfactory due to the severe side effects and increasingly acquired resistance. The development of novel and effective treatment strategies to overcome chemoresistance is urgent for cancer therapy. Metabolic reprogramming is one of the hallmarks of cancer. Cancer cells could rewire metabolic pathways to facilitate tumorigenesis, tumor progression, and metastasis, as well as chemoresistance. The metabolic reprogramming may serve as a promising therapeutic strategy and rekindle the research enthusiasm for overcoming chemoresistance. This review focuses on emerging mechanisms underlying rewired metabolic pathways for cancer chemoresistance in terms of glucose and energy, lipid, amino acid, and nucleotide metabolisms, as well as other related metabolisms. In particular, we highlight the potential of traditional Chinese medicine as a chemosensitizer for cancer chemotherapy from the metabolic perspective. The perspectives of metabolic targeting to chemoresistance are also discussed. In conclusion, the elucidation of the underlying metabolic reprogramming mechanisms by which cancer cells develop chemoresistance and traditional Chinese medicines resensitize chemotherapy would provide us a new insight into developing promising therapeutics and scientific evidence for clinical use of traditional Chinese medicine as a chemosensitizer for cancer therapy.

scholarly journals Targeting Cellular Metabolism Modulates Head and Neck Oncogenesis

2019 ◽  
Vol 20 (16) ◽  
pp. 3960 ◽  
Author(s):  
Yi-Ta Hsieh ◽  
Yi-Fen Chen ◽  
Shu-Chun Lin ◽  
Kuo-Wei Chang ◽  
Wan-Chun Li
Keyword(s):  
Head And Neck ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Molecular Level ◽  
Review Article ◽  
Metabolic Reprogramming ◽  
Prognostic Indicators ◽  
Normal Cells ◽  
Anti Cancer ◽  
Great Energy

Considering the great energy and biomass demand for cell survival, cancer cells exhibit unique metabolic signatures compared to normal cells. Head and neck squamous cell carcinoma (HNSCC) is one of the most prevalent neoplasms worldwide. Recent findings have shown that environmental challenges, as well as intrinsic metabolic manipulations, could modulate HNSCC experimentally and serve as clinic prognostic indicators, suggesting that a better understanding of dynamic metabolic changes during HNSCC development could be of great benefit for developing adjuvant anti-cancer schemes other than conventional therapies. However, the following questions are still poorly understood: (i) how does metabolic reprogramming occur during HNSCC development? (ii) how does the tumorous milieu contribute to HNSCC tumourigenesis? and (iii) at the molecular level, how do various metabolic cues interact with each other to control the oncogenicity and therapeutic sensitivity of HNSCC? In this review article, the regulatory roles of different metabolic pathways in HNSCC and its microenvironment in controlling the malignancy are therefore discussed in the hope of providing a systemic overview regarding what we knew and how cancer metabolism could be translated for the development of anti-cancer therapeutic reagents.

scholarly journals Emerging strategies to target cancer metabolism and improve radiation therapy outcomes

2020 ◽  
Vol 93 (1115) ◽  
pp. 20200067 ◽  
Author(s):  
Martin Kery ◽  
Ioanna Papandreou
Keyword(s):  
Oxidative Damage ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Glutamine Metabolism ◽  
Antioxidant Defenses ◽  
Tumor Control ◽  
Dna Integrity ◽  
Membrane Phospholipids ◽  
Nucleotide Synthesis ◽  
Treatment Protocols

Cancer-specific metabolic changes support the anabolic needs of the rapidly growing tumor, maintain a favorable redox balance, and help cells adapt to microenvironmental stresses like hypoxia and nutrient deprivation. Radiation is extensively applied in a large number of cancer treatment protocols but despite its curative potential, radiation resistance and treatment failures pose a serious problem. Metabolic control of DNA integrity and genomic stability can occur through multiple processes, encompassing cell cycle regulation, nucleotide synthesis, epigenetic regulation of gene activity, and antioxidant defenses. Given the important role of metabolic pathways in oxidative damage responses, it is necessary to assess the potential for tumor-specific radiosensitization by novel metabolism-targeted therapies. Additionally, there are opportunities to identify molecular and functional biomarkers of vulnerabilities to combination treatments, which could then inform clinical decisions. Here, we present a curated list of metabolic pathways in the context of ionizing radiation responses. Glutamine metabolism influences DNA damage responses by mechanisms such as synthesis of nucleotides for DNA repair or of glutathione for ROS detoxification. Repurposed oxygen consumption inhibitors have shown promising radiosensitizing activity against murine model tumors and are now in clinical trials. Production of 2-hydroxy glutarate by isocitrate dehydrogenase1/2 neomorphic oncogenic mutants interferes with the function of α-ketoglutarate-dependent enzymes and modulates Ataxia Telangiectasia Mutated (ATM) signaling and glutathione pools. Radiation-induced oxidative damage to membrane phospholipids promotes ferroptotic cell loss and cooperates with immunotherapies to improve tumor control. In summary, there are opportunities to enhance the efficacy of radiotherapy by exploiting cell-inherent vulnerabilities and dynamic microenvironmental components of the tumor.

scholarly journals SARS-CoV-2 and Glutamine: SARS-CoV-2 Triggered Pathogenesis via Metabolic Reprograming of Glutamine in Host Cells

2021 ◽  
Vol 7 ◽  
Author(s):  
Shiv Bharadwaj ◽  
Mahendra Singh ◽  
Nikhil Kirtipal ◽  
Sang Gu Kang
Keyword(s):  
Cancer Metabolism ◽  
Viral Infections ◽  
Mammalian Target Of Rapamycin ◽  
Metabolic Reprogramming ◽  
Host Cells ◽  
Glutamine Metabolism ◽  
Altered Glucose

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as coronavirus disease 2019 (COVID-19) pandemic, has killed more than a million people worldwide, and researchers are constantly working to develop therapeutics in the treatment and prevention of this new viral infection. To infect and induced pathogenesis as observed in other viral infections, we postulated that SARS-CoV-2 may also require an escalation in the anabolic metabolism, such as glucose and glutamine, to support its energy and biosynthetic requirements during the infection cycle. Recently, the requirement of altered glucose metabolism in SARS-CoV-2 pathogenesis was demonstrated, but the role of dysregulated glutamine metabolism is not yet mentioned for its infection. In this perspective, we have attempted to provide a summary of possible biochemical events on putative metabolic reprograming of glutamine in host cells upon SARS-CoV-2 infection by comparison to other viral infections/cancer metabolism and available clinical data or research on SARS-CoV-2 pathogenesis. This systematic hypothesis concluded the vital role of glutaminase-1 (GLS1), phosphoserine aminotransferase (PSAT1), hypoxia-inducible factor-1 alpha (HIF-1α), mammalian target of rapamycin complex 1 (mTORC1), glutamine-fructose amidotransferase 1/2 (GFAT1/2), and transcription factor Myc as key cellular factors to mediate and promote the glutamine metabolic reprogramming in SARS-CoV-2 infected cells. In absence of concrete data available for SARS-CoV-2 induced metabolic reprogramming of glutamine, this study efforts to connect the gaps with available clinical shreds of evidence in SARS-CoV-2 infection with altered glutamine metabolism and hopefully could be beneficial in the designing of strategic methods for therapeutic development with elucidation using in vitro or in vivo approaches.

scholarly journals The Crosstalk Between Signaling Pathways and Cancer Metabolism in Colorectal Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Kha Wai Hon ◽  
Syafiq Asnawi Zainal Abidin ◽  
Iekhsan Othman ◽  
Rakesh Naidu
Keyword(s):  
Colorectal Cancer ◽  
Signaling Pathways ◽  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Metabolic Reprogramming ◽  
Metabolic Inhibitors ◽  
Downstream Signaling ◽  
Insight Into

Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. Metabolic reprogramming represents an important cancer hallmark in CRC. Reprogramming core metabolic pathways in cancer cells, such as glycolysis, glutaminolysis, oxidative phosphorylation, and lipid metabolism, is essential to increase energy production and biosynthesis of precursors required to support tumor initiation and progression. Accumulating evidence demonstrates that activation of oncogenes and loss of tumor suppressor genes regulate metabolic reprogramming through the downstream signaling pathways. Protein kinases, such as AKT and c-MYC, are the integral components that facilitate the crosstalk between signaling pathways and metabolic pathways in CRC. This review provides an insight into the crosstalk between signaling pathways and metabolic reprogramming in CRC. Targeting CRC metabolism could open a new avenue for developing CRC therapy by discovering metabolic inhibitors and repurposing protein kinase inhibitors/monoclonal antibodies.

scholarly journals Phytochemicals targeting metabolic reprogramming in cancer: an assessment of role, mechanisms, pathways and therapeutic relevance

2020 ◽  
Author(s):  
Asifa Khan ◽  
Shumaila Siddiqui ◽  
Syed Husain ◽  
Sybille Mazurek ◽  
Mohammad Askandar Iqbal
Keyword(s):  
Metabolic Pathways ◽  
Cancer Metabolism ◽  
Therapeutic Benefit ◽  
Metabolic Reprogramming ◽  
Normal Cells ◽  
Cancer Hallmarks ◽  
Metabolic Transformation ◽  
Regulation Of Growth ◽  
Diverse Plant

The metabolism of cancer is remarkably different from that of normal cells and confers variety of benefits including the promotion of other cancer hallmarks. As the rewired metabolism is a near-universal property of cancer cells, efforts are underway to exploit metabolic vulnerabilities for therapeutic benefit. In the continued search for a safer and effective ways of cancer treatment, structurally diverse plant-based compounds have gained substantial attention. Here, we present an extensive assessment of the role of phytocompounds in modulating cancer metabolism and make a case for the use of plant-based compounds in targeting metabolic vulnerabilities of cancer. We discuss the interactions of phytocompounds with major metabolic pathways and evaluate the role of phytochemicals in the regulation of growth signaling and transcriptional programs involved in metabolic transformation of cancer. Lastly, we examine the potential of these compounds in clinical management of cancer along with limitations and challenges

scholarly journals Novel Liver X Receptor Ligand GAC0001E5 Disrupts Glutamine Metabolism and Induces Oxidative Stress in Pancreatic Cancer Cells

2020 ◽  
Vol 21 (24) ◽  
pp. 9622
Author(s):  
Shivangi Srivastava ◽  
Scott Widmann ◽  
Charles Ho ◽  
Donovan Nguyen ◽  
Alexis Nguyen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Cancer Metabolism ◽  
Target Genes ◽  
Metabolic Reprogramming ◽  
Glutamine Metabolism ◽  
Ductal Adenocarcinoma ◽  
Clinical Samples ◽  
Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer with a high mortality rate due to the lack of early detection and effective treatment options for advanced diseases. Metabolic reprogramming, a common hallmark of malignant transformation in pancreatic cancer, is critical for the growth and survival of cancer cells and a potential target mechanism for the treatment of pancreatic cancer. PDAC cells have upregulated glutamine metabolism to meet their biosynthetic and oxidative demands. Liver X receptors (LXRs) are ligand-dependent transcription factors involved in maintaining metabolic homeostasis. LXRs regulate critical cancer-related processes and pathways, including cholesterol, glucose and lipid metabolism, and inflammatory and immune responses. Analysis of transcriptomic data from PDAC clinical samples reveals overexpression of LXRs and their target genes in tumors as compared to normal tissue controls. Targeting LXRs with the novel LXR inverse agonist and degrader GAC0001E5 inhibited PDAC cell proliferation. Using a metabolomics approach, we discovered that 1E5 inhibits glutamine anaplerosis and induces oxidative stress, which are detrimental to PDAC cells. These findings highlight a novel role for LXR in regulating cancer metabolism and the potential application of LXR modulators in targeting cancer metabolism in pancreatic cancer and other malignancies.

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 Metabolic Reprogramming in COVID-19

2021 ◽  
Vol 22 (21) ◽  
pp. 11475
Author(s):  
Tao Shen ◽  
Tingting Wang
Keyword(s):  
Metabolic Disease ◽  
Immune Response ◽  
Fatty Acid ◽  
Metabolic Pathways ◽  
Critical Role ◽  
Therapeutic Agents ◽  
Metabolic Reprogramming ◽  
Adjuvant Therapies ◽  
Novel Biomarkers ◽  
Constituent Elements

Plenty of research has revealed virus induced alternations in metabolic pathways, which is known as metabolic reprogramming. Studies focusing on COVID-19 have uncovered significant changes in metabolism, resulting in the perspective that COVID-19 is a metabolic disease. Reprogramming of amino acid, glucose, cholesterol and fatty acid is distinctive characteristic of COVID-19 infection. These metabolic changes in COVID-19 have a critical role not only in producing energy and virus constituent elements, but also in regulating immune response, offering new insights into COVID-19 pathophysiology. Remarkably, metabolic reprogramming provides great opportunities for developing novel biomarkers and therapeutic agents for COVID-19 infection. Such novel agents are expected to be effective adjuvant therapies. In this review, we integrate present studies about major metabolic reprogramming in COVID-19, as well as the possibility of targeting reprogrammed metabolism to combat virus infection.

Sign in / Sign up

Export Citation Format

Share Document