Significance of Altered (Glucose) Metabolism in Cancers

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 39248

Special Issue Editors


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Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Qatar Foundation, Education City, Doha P.O. Box 24144, Qatar
Interests: tumor biology; metal toxicity; cellular pain modulation; anti-cancer drugs; natural compounds; phytochemicals
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Guest Editor
Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar (Medbay), Qatar Foundation, Education City, Doha P.O. Box 24144, Qatar
Interests: angiogenesis; autophagy; breast cancer; cancer (glucose) metabolism; cancer stem cells; diabetes; epithelial-mesenchymal-epithelial transition (EMT/MET); endoplasmic reticulum (ER) stress; metformin; therapeutic resistance; tumor microenvironment
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Musculoskeletal & Tumor Biology Research Group, Faculty of Medicine, Institute of Anatomy, Ludwig-Maximilians-University Munich, 80336 Munich, Germany.
Interests: inflammation; tumor biology; cancer; phytochemicals; resveratrol; curcumin; NF-kB; multicellular tumor microenvironment; cytokines; tissue engineering; 3D-alginate cultures

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European Association for Predictive, Preventive and Personalised Medicine, EPMA, 1160 Brussels, Belgium
Interests: cancer, chemoprevention; treatment, animal models; plant functional foods; phytochemicals; cell signaling; epigenetics of cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer, once considered as a pathological condition stemming from dysregulation of proliferation and apoptosis, has gained importance as a metabolic disease. Since the 1920s, when Otto Warburg reported higher rates of aerobic glycolysis, lactate accumulation and reduced oxidative phosphorylation (Warburg effect) in cancers, the concept that rapidly proliferating cancer cells adapt to meet their higher energy demand, through alterations in metabolism, has gained momentum.

Glucose/carbohydrate metabolism is the most studied adaptation in terms of the metabolic alterations in cancers. However, more recently, in the neoplastic tissues, other dimensions of the rewired metabolism, such as 1) changes in amino acid/protein, lipid and nucleotide metabolism, 2) utilization of glutamine and 3) isoforms of several metabolic enzymes that support tumorigenesis, cancer progression and drug resistance, has garnered attention.

This Special Issue will 1) provide an in-depth understanding of the molecular mechanisms of the altered/adaptive metabolism in cancers and its impact on tumor initiation, progression and response to therapy, 2) identify new targets for, therapeutic intervention, overcoming therapeutic resistance, metastasis and relapse of the disease, and 3) facilitate possible re-purposing of drugs used in the treatment of metabolic disorders as suitable anti-cancer agents.

Prof. Dr. Dietrich Büsselberg
Dr. Samson Mathews Samuel
Prof. Dr. Mehdi Shakibaei
Prof. Dr. Peter Kubatka
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 short 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

  • glucose metabolism in tumors
  • alternative metabolic pathways in cancers
  • antioxidants
  • biomarkers
  • cancers
  • cancer stem cells
  • chemo- and radio-therapeutic resistance
  • diagnosis and prognosis
  • drug design and delivery
  • drug re-purposing
  • epithelial–mesenchymal–epithelial transition (EMT/MET)
  • mitochondria
  • oxidative stress
  • reactive oxygen species
  • relapse
  • tumor microenvironment
  • Warburg effect

Published Papers (7 papers)

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Editorial

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6 pages, 654 KiB  
Editorial
The Juggernaut of Adaptive Metabolism in Cancers: Implications and Therapeutic Targets
by Samson Mathews Samuel, Peter Kubatka, Mehdi Shakibaei and Dietrich Büsselberg
Cancers 2022, 14(21), 5202; https://doi.org/10.3390/cancers14215202 - 23 Oct 2022
Cited by 1 | Viewed by 1234
Abstract
The disease of cancer instills a sense of fear and dread among patients and the next of kin who are indirectly affected by the deteriorating quality of life of their loved ones [...] Full article
(This article belongs to the Special Issue Significance of Altered (Glucose) Metabolism in Cancers)
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Research

Jump to: Editorial, Review

19 pages, 2935 KiB  
Article
Expression of 3-Methylcrotonyl-CoA Carboxylase in Brain Tumors and Capability to Catabolize Leucine by Human Neural Cancer Cells
by Eduard Gondáš, Alžbeta Kráľová Trančíková, Eva Baranovičová, Jakub Šofranko, Jozef Hatok, Bhavani S. Kowtharapu, Tomáš Galanda, Dušan Dobrota, Peter Kubatka, Dietrich Busselberg and Radovan Murín
Cancers 2022, 14(3), 585; https://doi.org/10.3390/cancers14030585 - 24 Jan 2022
Cited by 11 | Viewed by 3455
Abstract
Leucine is an essential, ketogenic amino acid with proteinogenic, metabolic, and signaling roles. It is readily imported from the bloodstream into the brain parenchyma. Therefore, it could serve as a putative substrate that is complementing glucose for sustaining the metabolic needs of brain [...] Read more.
Leucine is an essential, ketogenic amino acid with proteinogenic, metabolic, and signaling roles. It is readily imported from the bloodstream into the brain parenchyma. Therefore, it could serve as a putative substrate that is complementing glucose for sustaining the metabolic needs of brain tumor cells. Here, we investigated the ability of cultured human cancer cells to metabolize leucine. Indeed, cancer cells dispose of leucine from their environment and enrich their media with the metabolite 2-oxoisocaproate. The enrichment of the culture media with a high level of leucine stimulated the production of 3-hydroxybutyrate. When 13C6-leucine was offered, it led to an increased appearance of the heavier citrate isotope with a molar mass greater by two units in the culture media. The expression of 3-methylcrotonyl-CoA carboxylase (MCC), an enzyme characteristic for the irreversible part of the leucine catabolic pathway, was detected in cultured cancer cells and human tumor samples by immunoprobing methods. Our results demonstrate that these cancer cells can catabolize leucine and furnish its carbon atoms into the tricarboxylic acid (TCA) cycle. Furthermore, the release of 3-hydroxybutyrate and citrate by cancer cells suggests their capability to exchange these metabolites with their milieu and the capability to participate in their metabolism. This indicates that leucine could be an additional substrate for cancer cell metabolism in the brain parenchyma. In this way, leucine could potentially contribute to the synthesis of metabolites such as lipids, which require the withdrawal of citrate from the TCA cycle. Full article
(This article belongs to the Special Issue Significance of Altered (Glucose) Metabolism in Cancers)
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Review

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52 pages, 3094 KiB  
Review
Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue
by Ibrahim AlZaim, Aya Al-Saidi, Safaa H. Hammoud, Nadine Darwiche, Yusra Al-Dhaheri, Ali H. Eid and Ahmed F. El-Yazbi
Cancers 2022, 14(7), 1679; https://doi.org/10.3390/cancers14071679 - 25 Mar 2022
Cited by 6 | Viewed by 5073
Abstract
The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only [...] Read more.
The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states. Full article
(This article belongs to the Special Issue Significance of Altered (Glucose) Metabolism in Cancers)
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23 pages, 448 KiB  
Review
Advancing Cancer Treatment by Targeting Glutamine Metabolism—A Roadmap
by Anna Halama and Karsten Suhre
Cancers 2022, 14(3), 553; https://doi.org/10.3390/cancers14030553 - 22 Jan 2022
Cited by 42 | Viewed by 6028
Abstract
Tumor growth and metastasis strongly depend on adapted cell metabolism. Cancer cells adjust their metabolic program to their specific energy needs and in response to an often challenging tumor microenvironment. Glutamine metabolism is one of the metabolic pathways that can be successfully targeted [...] Read more.
Tumor growth and metastasis strongly depend on adapted cell metabolism. Cancer cells adjust their metabolic program to their specific energy needs and in response to an often challenging tumor microenvironment. Glutamine metabolism is one of the metabolic pathways that can be successfully targeted in cancer treatment. The dependence of many hematological and solid tumors on glutamine is associated with mitochondrial glutaminase (GLS) activity that enables channeling of glutamine into the tricarboxylic acid (TCA) cycle, generation of ATP and NADPH, and regulation of glutathione homeostasis and reactive oxygen species (ROS). Small molecules that target glutamine metabolism through inhibition of GLS therefore simultaneously limit energy availability and increase oxidative stress. However, some cancers can reprogram their metabolism to evade this metabolic trap. Therefore, the effectiveness of treatment strategies that rely solely on glutamine inhibition is limited. In this review, we discuss the metabolic and molecular pathways that are linked to dysregulated glutamine metabolism in multiple cancer types. We further summarize and review current clinical trials of glutaminolysis inhibition in cancer patients. Finally, we put into perspective strategies that deploy a combined treatment targeting glutamine metabolism along with other molecular or metabolic pathways and discuss their potential for clinical applications. Full article
(This article belongs to the Special Issue Significance of Altered (Glucose) Metabolism in Cancers)
35 pages, 1533 KiB  
Review
Resveratrol’s Anti-Cancer Effects through the Modulation of Tumor Glucose Metabolism
by Aranka Brockmueller, Saba Sameri, Alena Liskova, Kevin Zhai, Elizabeth Varghese, Samson Mathews Samuel, Dietrich Büsselberg, Peter Kubatka and Mehdi Shakibaei
Cancers 2021, 13(2), 188; https://doi.org/10.3390/cancers13020188 - 7 Jan 2021
Cited by 51 | Viewed by 7640
Abstract
Tumor cells develop several metabolic reprogramming strategies, such as increased glucose uptake and utilization via aerobic glycolysis and fermentation of glucose to lactate; these lead to a low pH environment in which the cancer cells thrive and evade apoptosis. These characteristics of tumor [...] Read more.
Tumor cells develop several metabolic reprogramming strategies, such as increased glucose uptake and utilization via aerobic glycolysis and fermentation of glucose to lactate; these lead to a low pH environment in which the cancer cells thrive and evade apoptosis. These characteristics of tumor cells are known as the Warburg effect. Adaptive metabolic alterations in cancer cells can be attributed to mutations in key metabolic enzymes and transcription factors. The features of the Warburg phenotype may serve as promising markers for the early detection and treatment of tumors. Besides, the glycolytic process of tumors is reversible and could represent a therapeutic target. So-called mono-target therapies are often unsafe and ineffective, and have a high prevalence of recurrence. Their success is hindered by the ability of tumor cells to simultaneously develop multiple chemoresistance pathways. Therefore, agents that modify several cellular targets, such as energy restriction to target tumor cells specifically, have therapeutic potential. Resveratrol, a natural active polyphenol found in grapes and red wine and used in many traditional medicines, is known for its ability to target multiple components of signaling pathways in tumors, leading to the suppression of cell proliferation, activation of apoptosis, and regression in tumor growth. Here, we describe current knowledge on the various mechanisms by which resveratrol modulates glucose metabolism, its potential as an imitator of caloric restriction, and its therapeutic capacity in tumors. Full article
(This article belongs to the Special Issue Significance of Altered (Glucose) Metabolism in Cancers)
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27 pages, 1634 KiB  
Review
Flavonoids Targeting HIF-1: Implications on Cancer Metabolism
by Marek Samec, Alena Liskova, Lenka Koklesova, Sandra Mersakova, Jan Strnadel, Karol Kajo, Martin Pec, Kevin Zhai, Karel Smejkal, Sepideh Mirzaei, Kiavash Hushmandi, Milad Ashrafizadeh, Luciano Saso, Aranka Brockmueller, Mehdi Shakibaei, Dietrich Büsselberg and Peter Kubatka
Cancers 2021, 13(1), 130; https://doi.org/10.3390/cancers13010130 - 3 Jan 2021
Cited by 52 | Viewed by 7538
Abstract
Tumor hypoxia is described as an oxygen deprivation in malignant tissue. The hypoxic condition is a consequence of an imbalance between rapidly proliferating cells and a vascularization that leads to lower oxygen levels in tumors. Hypoxia-inducible factor 1 (HIF-1) is an essential transcription [...] Read more.
Tumor hypoxia is described as an oxygen deprivation in malignant tissue. The hypoxic condition is a consequence of an imbalance between rapidly proliferating cells and a vascularization that leads to lower oxygen levels in tumors. Hypoxia-inducible factor 1 (HIF-1) is an essential transcription factor contributing to the regulation of hypoxia-associated genes. Some of these genes modulate molecular cascades associated with the Warburg effect and its accompanying pathways and, therefore, represent promising targets for cancer treatment. Current progress in the development of therapeutic approaches brings several promising inhibitors of HIF-1. Flavonoids, widely occurring in various plants, exert a broad spectrum of beneficial effects on human health, and are potentially powerful therapeutic tools against cancer. Recent evidences identified numerous natural flavonoids and their derivatives as inhibitors of HIF-1, associated with the regulation of critical glycolytic components in cancer cells, including pyruvate kinase M2(PKM2), lactate dehydrogenase (LDHA), glucose transporters (GLUTs), hexokinase II (HKII), phosphofructokinase-1 (PFK-1), and pyruvate dehydrogenase kinase (PDK). Here, we discuss the results of most recent studies evaluating the impact of flavonoids on HIF-1 accompanied by the regulation of critical enzymes contributing to the Warburg phenotype. Besides, flavonoid effects on glucose metabolism via regulation of HIF-1 activity represent a promising avenue in cancer-related research. At the same time, only more-in depth investigations can further elucidate the mechanistic and clinical connections between HIF-1 and cancer metabolism. Full article
(This article belongs to the Special Issue Significance of Altered (Glucose) Metabolism in Cancers)
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52 pages, 5993 KiB  
Review
Counteracting Chemoresistance with Metformin in Breast Cancers: Targeting Cancer Stem Cells
by Samson Mathews Samuel, Elizabeth Varghese, Lenka Koklesová, Alena Líšková, Peter Kubatka and Dietrich Büsselberg
Cancers 2020, 12(9), 2482; https://doi.org/10.3390/cancers12092482 - 1 Sep 2020
Cited by 32 | Viewed by 6933
Abstract
Despite the leaps and bounds in achieving success in the management and treatment of breast cancers through surgery, chemotherapy, and radiotherapy, breast cancer remains the most frequently occurring cancer in women and the most common cause of cancer-related deaths among women. Systemic therapeutic [...] Read more.
Despite the leaps and bounds in achieving success in the management and treatment of breast cancers through surgery, chemotherapy, and radiotherapy, breast cancer remains the most frequently occurring cancer in women and the most common cause of cancer-related deaths among women. Systemic therapeutic approaches, such as chemotherapy, although beneficial in treating and curing breast cancer subjects with localized breast tumors, tend to fail in metastatic cases of the disease due to (a) an acquired resistance to the chemotherapeutic drug and (b) the development of intrinsic resistance to therapy. The existence of cancer stem cells (CSCs) plays a crucial role in both acquired and intrinsic chemoresistance. CSCs are less abundant than terminally differentiated cancer cells and confer chemoresistance through a unique altered metabolism and capability to evade the immune response system. Furthermore, CSCs possess active DNA repair systems, transporters that support multidrug resistance (MDR), advanced detoxification processes, and the ability to self-renew and differentiate into tumor progenitor cells, thereby supporting cancer invasion, metastasis, and recurrence/relapse. Hence, current research is focusing on targeting CSCs to overcome resistance and improve the efficacy of the treatment and management of breast cancer. Studies revealed that metformin (1, 1-dimethylbiguanide), a widely used anti-hyperglycemic agent, sensitizes tumor response to various chemotherapeutic drugs. Metformin selectively targets CSCs and improves the hypoxic microenvironment, suppresses the tumor metastasis and inflammation, as well as regulates the metabolic programming, induces apoptosis, and reverses epithelial–mesenchymal transition and MDR. Here, we discuss cancer (breast cancer) and chemoresistance, the molecular mechanisms of chemoresistance in breast cancers, and metformin as a chemo-sensitizing/re-sensitizing agent, with a particular focus on breast CSCs as a critical contributing factor to acquired and intrinsic chemoresistance. The review outlines the prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer/chemo-sensitizing drug in the treatment of breast cancer. It intends to provide a rationale for the use of metformin as a combinatory therapy in a clinical setting. Full article
(This article belongs to the Special Issue Significance of Altered (Glucose) Metabolism in Cancers)
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