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Cancers
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Glutamine Metabolism in the Onset and Progression of Tumorigenesis
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Glutamine Metabolism in the Onset and Progression of Tumorigenesis

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (15 July 2024) | Viewed by 9405

Special Issue Editors

Prof. Dr. Javier Marquez

E-Mail Website
Guest Editor
1. Departamento de Biología Molecular y Bioquímica, Canceromics Lab, Universidad de Málaga, 29071 Málaga, Spain
2. Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain
Interests: canceromics; cancer metabolic reprogramming; gene therapy; tumor nitrogen metabolism
Special Issues, Collections and Topics in MDPI journals
Dr. José Ángel Campos Sandoval

E-Mail Website
Guest Editor
1. Departamento de Biología Molecular y Bioquímica, Canceromics Lab, Universidad de Málaga, 29071 Málaga, Spain
2. Instituto de Investigación Biomédica de Málaga (IBIMA), 29010 Málaga, Spain
Interests: cancer omics; cancer metabolic reprogramming; tumor nitrogen metabolism; structure-function studies; drug design
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer is one of the leading causes of death worldwide. There is an urgent need for new strategies to prevent and treat cancer. These include overcoming the metabolic reprogramming and drug resistance phenomena frequently found in cancer therapy.

Metabolic reprogramming in cancer targets glutamine metabolism as a key mechanism to provide energy, biosynthetic precursors and redox requirements to allow the massive proliferation of tumor cells. Glutamine is also a signaling molecule involved in essential pathways regulated by oncogenes and tumor suppressor factors. Glutamine transporters, glutaminase isoenzymes and other metabolic enzymes are critical proteins to control glutaminolysis, a key metabolic pathway for cell proliferation and survival that directs neoplasms’ fate. Adaptive glutamine metabolism can be altered by different metabolic therapies, including combination therapies that can evoke synergistic effects for the therapy of cancer patients.

This Special Issue will highlight sound papers related to cancer glutamine metabolism and its critical role for tumor growth and proliferation, including new therapeutic options aimed at interfering with the strong dependence on glutamine shown by many types of cancers.

Prof. Dr. Javier Marquez
Dr. José Ángel Campos Sandoval
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • glutamine addiction
  • glutamine signaling
  • oncogenesis
  • targeted/combined therapy
  • glutamine carriers
  • glutaminases
  • ROS
  • oxidative stress

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Published Papers (4 papers)

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Research

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12 pages, 1557 KiB  
Article
Tripartite Motif-Containing 2, a Glutamine Metabolism-Associated Protein, Predicts Poor Patient Outcome in Triple-Negative Breast Cancer Treated with Chemotherapy
by Brendah K. Masisi, Rokaya El Ansari, Lutfi Alfarsi, Ali Fakroun, Busra Erkan, Asmaa Ibrahim, Michael Toss, Ian O. Ellis, Emad A. Rakha and Andrew R. Green
Cancers 2024, 16(11), 1949; https://doi.org/10.3390/cancers16111949 - 21 May 2024
Viewed by 1115
Abstract
Background: Breast cancer (BC) remains heterogeneous in terms of prognosis and response to treatment. Metabolic reprogramming is a critical part of oncogenesis and a potential therapeutic target. Glutaminase (GLS), which generates glutamate from glutamine, plays a role in triple-negative breast cancer (TNBC). However, [...] Read more.
Background: Breast cancer (BC) remains heterogeneous in terms of prognosis and response to treatment. Metabolic reprogramming is a critical part of oncogenesis and a potential therapeutic target. Glutaminase (GLS), which generates glutamate from glutamine, plays a role in triple-negative breast cancer (TNBC). However, targeting GLS directly may be difficult, as it is essential for normal cell function. This study aimed to determine potential targets in BC associated with glutamine metabolism and evaluate their prognostic value in BC. Methods: The iNET model was used to identify genes in BC that are associated with GLS using RNA-sequencing data. The prognostic significance of tripartite motif-containing 2 (TRIM2) mRNA was assessed in BC transcriptomic data (n = 16,575), and TRIM2 protein expression was evaluated using immunohistochemistry (n = 749) in patients with early-stage invasive breast cancer with long-term follow-up. The associations between TRIM2 expression and clinicopathological features and patient outcomes were evaluated. Results: Pathway analysis identified TRIM2 expression as an important gene co-expressed with high GLS expression in BC. High TRIM2 mRNA and TRIM2 protein expression were associated with TNBC (p < 0.01). TRIM2 was a predictor of poor distant metastasis-free survival (DMFS) in TNBC (p < 0.01), and this was independent of established prognostic factors (p < 0.05), particularly in those who received chemotherapy (p < 0.05). In addition, TRIM2 was a predictor of shorter DMFS in TNBC treated with chemotherapy (p < 0.01). Conclusions: This study provides evidence of an association between TRIM2 and poor patient outcomes in TNBC, especially those treated with chemotherapy. The molecular mechanisms and functional behaviour of TRIM2 and the functional link with GLS in BC warrant further exploration using in vitro models. Full article
(This article belongs to the Special Issue Glutamine Metabolism in the Onset and Progression of Tumorigenesis)
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21 pages, 7719 KiB  
Article
Metabolic Adjustments following Glutaminase Inhibition by CB-839 in Glioblastoma Cell Lines
by Juan De los Santos-Jiménez, Tracy Rosales, Bookyung Ko, José A. Campos-Sandoval, Francisco J. Alonso, Javier Márquez, Ralph J. DeBerardinis and José M. Matés
Cancers 2023, 15(2), 531; https://doi.org/10.3390/cancers15020531 - 15 Jan 2023
Cited by 15 | Viewed by 3339
Abstract
Most tumor cells can use glutamine (Gln) for energy generation and biosynthetic purposes. Glutaminases (GAs) convert Gln into glutamate and ammonium. In humans, GAs are encoded by two genes: GLS and GLS2. In glioblastoma, GLS is commonly overexpressed and considered pro-oncogenic. We [...] Read more.
Most tumor cells can use glutamine (Gln) for energy generation and biosynthetic purposes. Glutaminases (GAs) convert Gln into glutamate and ammonium. In humans, GAs are encoded by two genes: GLS and GLS2. In glioblastoma, GLS is commonly overexpressed and considered pro-oncogenic. We studied the metabolic effects of inhibiting GLS activity in T98G, LN229, and U87MG human glioblastoma cell lines by using the inhibitor CB-839. We performed metabolomics and isotope tracing experiments using U-13C-labeled Gln, as well as 15N-labeled Gln in the amide group, to determine the metabolic fates of Gln carbon and nitrogen atoms. In the presence of the inhibitor, the results showed an accumulation of Gln and lower levels of tricarboxylic acid cycle intermediates, and aspartate, along with a decreased oxidative labeling and diminished reductive carboxylation-related labeling of these metabolites. Additionally, CB-839 treatment caused decreased levels of metabolites from pyrimidine biosynthesis and an accumulation of intermediate metabolites in the de novo purine nucleotide biosynthesis pathway. The levels of some acetylated and methylated metabolites were significantly increased, including acetyl-carnitine, trimethyl-lysine, and 5-methylcytosine. In conclusion, we analyzed the metabolic landscape caused by the GLS inhibition of CB-839 in human glioma cells, which might lead to the future development of new combination therapies with CB-839. Full article
(This article belongs to the Special Issue Glutamine Metabolism in the Onset and Progression of Tumorigenesis)
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Review

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28 pages, 1533 KiB  
Review
Glutamine Metabolism and Prostate Cancer
by Holger H. H. Erb, Nikita Polishchuk, Oleh Stasyk, Uğur Kahya, Matthias M. Weigel and Anna Dubrovska
Cancers 2024, 16(16), 2871; https://doi.org/10.3390/cancers16162871 - 18 Aug 2024
Cited by 1 | Viewed by 2100
Abstract
Glutamine (Gln) is a non-essential amino acid that is involved in the development and progression of several malignancies, including prostate cancer (PCa). While Gln is non-essential for non-malignant prostate epithelial cells, PCa cells become highly dependent on an exogenous source of Gln. The [...] Read more.
Glutamine (Gln) is a non-essential amino acid that is involved in the development and progression of several malignancies, including prostate cancer (PCa). While Gln is non-essential for non-malignant prostate epithelial cells, PCa cells become highly dependent on an exogenous source of Gln. The Gln metabolism in PCa is tightly controlled by well-described oncogenes such as MYC, AR, and mTOR. These oncogenes contribute to therapy resistance and progression to the aggressive castration-resistant PCa. Inhibition of Gln catabolism impedes PCa growth, survival, and tumor-initiating potential while sensitizing the cells to radiotherapy. Therefore, given its significant role in tumor growth, targeting Gln metabolism is a promising approach for developing new therapeutic strategies. Ongoing clinical trials evaluate the safety and efficacy of Gln catabolism inhibitors in combination with conventional and targeted therapies in patients with various solid tumors, including PCa. Further understanding of how PCa cells metabolically interact with their microenvironment will facilitate the clinical translation of Gln inhibitors and help improve therapeutic outcomes. This review focuses on the role of Gln in PCa progression and therapy resistance and provides insights into current clinical trials. Full article
(This article belongs to the Special Issue Glutamine Metabolism in the Onset and Progression of Tumorigenesis)
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22 pages, 2643 KiB  
Review
Two Faces of Glutaminase GLS2 in Carcinogenesis
by Joanna Buczkowska and Monika Szeliga
Cancers 2023, 15(23), 5566; https://doi.org/10.3390/cancers15235566 - 24 Nov 2023
Cited by 6 | Viewed by 1949
Abstract
In rapidly proliferating cancer cells, glutamine is a major source of energy and building blocks. Increased glutamine uptake and enhanced glutaminolysis are key metabolic features of many cancers. Glutamine is metabolized by glutaminase (GA), which is encoded by two genes: GLS and GLS2 [...] Read more.
In rapidly proliferating cancer cells, glutamine is a major source of energy and building blocks. Increased glutamine uptake and enhanced glutaminolysis are key metabolic features of many cancers. Glutamine is metabolized by glutaminase (GA), which is encoded by two genes: GLS and GLS2. In contrast to isoforms arising from the GLS gene, which clearly act as oncoproteins, the role of GLS2 products in tumorigenesis is far from well understood. While in some cancer types GLS2 is overexpressed and drives cancer development, in some other types it is downregulated and behaves as a tumor suppressor gene. In this review, we describe the essential functions and regulatory mechanisms of human GLS2 and the cellular compartments in which GLS2 has been localized. Furthermore, we present the context-dependent oncogenic and tumor-suppressor properties of GLS2, and delve into the mechanisms underlying these phenomena. Full article
(This article belongs to the Special Issue Glutamine Metabolism in the Onset and Progression of Tumorigenesis)
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