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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 78458

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Special Issue Editors

Dr. Maria E. Mycielska

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Guest Editor

Department of Surgery, University Medical Centre Regensburg, Germany
Interests: prostate cancer; metabolism; transporter; citrate; cancer associated stroma; metastasis; mitochondria

Dr. Sebastian Haferkamp

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Department of Dermatology, University Medical Centre, Regensburg, Germany
Interests: cutaneous melanoma; metabolism; metastasis
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Prof. Dr. Eric Parkinson

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Centre for Immunobiology and Regenerative Medicine, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, UK
Interests: ageing; senescence; oral cancer; squamous cell carcinoma; metabolism; cell cycle
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer cells require excess energy and metabolite synthesis to successfully grow and metastasize. Therefore, their metabolism has to be particularly efficient. Moreover, changing extracellular conditions require that cancer cells have significant flexibility and use different pathways and supplies to supplement potentially missing metabolites. To secure the necessary substrates, cancer cells rely on the surrounding stroma and newly formed blood vessels. They also modify their metabolism and involve the tumor environment to increase their resistance to anticancer therapies. Not surprisingly, cancer cell metabolism differs significantly from its healthy counterpart and is exploited diagnostically and therapeutically. For this Special Issue, we invite the submission of research articles and reviews on metabolic mechanisms supporting tumor metastases, organ colonization, escape from immune defense, and therapeutic resistance as well as metabolic interactions with the stroma. We would like input from basic, translational, and preclinical studies.

Dr. Maria E. Mycielska
Dr. Sebastian Haferkamp
Prof. Dr. Eric Parkinson
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

cancer
metabolism
metastasis
colonization
therapy resistance
cancer associated stroma
immune cells
diagnostics

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

3 pages, 191 KiB

Open AccessEditorial

Cancer Cell Metabolism

by Eric K. Parkinson, Sebastian Haferkamp and Maria E. Mycielska

Int. J. Mol. Sci. 2022, 23(13), 7210; https://doi.org/10.3390/ijms23137210 - 29 Jun 2022

Cited by 2 | Viewed by 2085

Abstract

Cancer metabolism has been of interest for decades; however, the recent development of sophisticated techniques such as metabolomics or lipidomics have significantly increased our understanding of processes taking place in tumour cells [...] Full article

(This article belongs to the Special Issue Cancer Cell Metabolism)

Research

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39 pages, 11096 KiB

Open AccessArticle

Synergistic Growth Inhibition of HT-29 Colon and MCF-7 Breast Cancer Cells with Simultaneous and Sequential Combinations of Antineoplastics and CNS Drugs

by Diana Duarte, Armando Cardoso and Nuno Vale

Int. J. Mol. Sci. 2021, 22(14), 7408; https://doi.org/10.3390/ijms22147408 - 10 Jul 2021

Cited by 38 | Viewed by 6728

Abstract

Several central nervous system (CNS) drugs exhibit potent anti-cancer activities. This study aimed to design a novel model of combination that combines different CNS agents and antineoplastic drugs (5-fluorouracil (5-FU) and paclitaxel (PTX)) for colorectal and breast cancer therapy, respectively. Cytotoxic effects of 5-FU and PTX alone and in combination with different CNS agents were evaluated on HT-29 colon and MCF-7 breast cancer cells, respectively. Three antimalarials alone and in combination with 5-FU were also evaluated in HT-29 cells. Different schedules and concentrations in a fixed ratio were added to the cultured cells and incubated for 48 h. Cell viability was evaluated using MTT and SRB assays. Synergism was evaluated using the Chou-Talalay, Bliss Independence and HSA methods. Our results demonstrate that fluphenazine, fluoxetine and benztropine have enhanced anticancer activity when used alone as compared to being used in combination, making them ideal candidates for drug repurposing in colorectal cancer (CRC). Regarding MCF-7 cells, sertraline was the most promising candidate alone for drug repurposing, with the lowest IC₅₀ value. For HT-29 cells, the CNS drugs sertraline and thioridazine in simultaneous combination with 5-FU demonstrated the strongest synergism among all combinations. In MCF-7 breast cancer cells, the combination of fluoxetine, fluphenazine and benztropine with PTX resulted in synergism for all concentrations below IC₅₀. We also found that the antimalarial artesunate administration prior to 5-FU produces better results in reducing HT-29 cell viability than the inverse drug schedule or the simultaneous combination. These results demonstrate that CNS drugs activity differs between the two selected cell lines, both alone and in combination, and support that some CNS agents may be promising candidates for drug repurposing in these types of cancers. Additionally, these results demonstrate that 5-FU or a combination of PTX with CNS drugs should be further evaluated. These results also demonstrate that antimalarial drugs may also be used as antitumor agents in colorectal cancer, besides breast cancer. Full article

(This article belongs to the Special Issue Cancer Cell Metabolism)

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15 pages, 5715 KiB

Open AccessArticle

Targeting the NAD Salvage Synthesis Pathway as a Novel Therapeutic Strategy for Osteosarcomas with Low NAPRT Expression

by Natasja Franceschini, Jan Oosting, Maud Tamsma, Bertine Niessen, Inge Briaire-de Bruijn, Brendy van den Akker, Alwine B. Kruisselbrink, Ieva Palubeckaitė, Judith V. M. G. Bovée and Anne-Marie Cleton-Jansen

Int. J. Mol. Sci. 2021, 22(12), 6273; https://doi.org/10.3390/ijms22126273 - 10 Jun 2021

Cited by 9 | Viewed by 3214

Abstract

For osteosarcoma (OS), the most common primary malignant bone tumor, overall survival has hardly improved over the last four decades. Especially for metastatic OS, novel therapeutic targets are urgently needed. A hallmark of cancer is aberrant metabolism, which justifies targeting metabolic pathways as a promising therapeutic strategy. One of these metabolic pathways, the NAD+ synthesis pathway, can be considered as a potential target for OS treatment. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in the classical salvage pathway for NAD+ synthesis, and NAMPT is overexpressed in OS. In this study, five OS cell lines were treated with the NAMPT inhibitor FK866, which was shown to decrease nuclei count in a 2D in vitro model without inducing caspase-driven apoptosis. The reduction in cell viability by FK866 was confirmed in a 3D model of OS cell lines (n = 3). Interestingly, only OS cells with low nicotinic acid phosphoribosyltransferase domain containing 1 (NAPRT1) RNA expression were sensitive to NAMPT inhibition. Using a publicly available (Therapeutically Applicable Research to Generate Effective Treatments (TARGET)) and a previously published dataset, it was shown that in OS cell lines and primary tumors, low NAPRT1 RNA expression correlated with NAPRT1 methylation around the transcription start site. These results suggest that targeting NAMPT in osteosarcoma could be considered as a novel therapeutic strategy, where low NAPRT expression can serve as a biomarker for the selection of eligible patients. Full article

(This article belongs to the Special Issue Cancer Cell Metabolism)

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21 pages, 9557 KiB

Open AccessArticle

Loss of Fer Jeopardizes Metabolic Plasticity and Mitochondrial Homeostasis in Lung and Breast Carcinoma Cells

by Linoy Mehazri, Sally Shpungin, Shai Bel and Uri Nir

Int. J. Mol. Sci. 2021, 22(7), 3387; https://doi.org/10.3390/ijms22073387 - 25 Mar 2021

Cited by 7 | Viewed by 3618

Abstract

Metabolic plasticity is a hallmark of the ability of metastatic cancer cells to survive under stressful conditions. The intracellular Fer kinase is a selective constituent of the reprogramed mitochondria and metabolic system of cancer cells. In the current work, we deciphered the modulatory roles of Fer in the reprogrammed metabolic systems of metastatic, lung (H358), non-small cell lung cancer (NSCLC), and breast (MDA-MB-231), triple-negative breast cancer (TNBC), carcinoma cells. We show that H358 cells devoid of Fer (H358ΔFer), strictly depend on glucose for their proliferation and growth, and fail to compensate for glucose withdrawal by oxidizing and metabolizing glutamine. Furthermore, glucose deficiency caused increased reactive oxygen species (ROS) production and induction of a DNA damage response (DDR), accompanied by the onset of apoptosis and attenuated cell-cycle progression. Analysis of mitochondrial function revealed impaired respiratory and electron transport chain (ETC) complex 1 (comp. I) activity in the Fer-deficient H358ΔFer cells. This was manifested by decreased levels of NAD⁺ and ATP and relatively low abundance of tricarboxylic acid (TCA) cycle metabolites. Impaired electron transport chain comp. I activity and dependence on glucose were also confirmed in Fer-deficient, MDA-MB-231ΔFer cells. Although both H358ΔFer and MDA-MB-231ΔFer cells showed a decreased aspartate level, this seemed to be compensated by the predominance of pyrimidines synthesis over the urea cycle progression. Notably, absence of Fer significantly impeded the growth of H358ΔFer and MDA-MB-231ΔFer xenografts in mice provided with a carb-deficient, ketogenic diet. Thus, Fer plays a key role in the sustention of metabolic plasticity of malignant cells. In compliance with this notion, targeting Fer attenuates the progression of H358 and MDA-MB-231 tumors, an effect that is potentiated by a glucose-restrictive diet. Full article

(This article belongs to the Special Issue Cancer Cell Metabolism)

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13 pages, 1626 KiB

Open AccessArticle

The Interplay between Oxidative Phosphorylation and Glycolysis as a Potential Marker of Bladder Cancer Progression

by Greta Petrella, Giorgia Ciufolini, Riccardo Vago and Daniel Oscar Cicero

Int. J. Mol. Sci. 2020, 21(21), 8107; https://doi.org/10.3390/ijms21218107 - 30 Oct 2020

Cited by 20 | Viewed by 3818

Abstract

Urothelial bladder cancer (UBC) is the most common tumor of the urinary system. One of the biggest problems related to this disease is the lack of markers that can anticipate the progression of the cancer. Genomics and transcriptomics have greatly improved the prediction of risk of recurrence and progression. Further progress can be expected including information from other omics sciences such as metabolomics. In this study, we used ¹H-NMR to characterize the intake of nutrients and the excretion of products in the extracellular medium of three UBC cell lines, which are representatives of low-grade tumors, RT4, high-grade, 5637, and a cell line that shares genotypic features with both, RT112. We have observed that RT4 cells show an activated oxidative phosphorylation, 5637 cells depend mostly on glycolysis to grow, while RT112 cells show a mixed metabolic state. Our results reveal the relative importance of glycolysis and oxidative phosphorylation in the growth and maintenance of different UBC cell lines, and the relationship with their genomic signatures. They suggest that cell lines associated with a low risk of progression present an activated oxidative metabolic state, while those associated with a high risk present a non-oxidative state and high glycolytic activity. Full article

(This article belongs to the Special Issue Cancer Cell Metabolism)

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Review

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22 pages, 1372 KiB

Open AccessReview

More Than Meets the Eye Regarding Cancer Metabolism

by Anna Kubicka, Karolina Matczak and Magdalena Łabieniec-Watała

Int. J. Mol. Sci. 2021, 22(17), 9507; https://doi.org/10.3390/ijms22179507 - 1 Sep 2021

Cited by 15 | Viewed by 4771

Abstract

In spite of the continuous improvement in our knowledge of the nature of cancer, the causes of its formation and the development of new treatment methods, our knowledge is still incomplete. A key issue is the difference in metabolism between normal and cancer cells. The features that distinguish cancer cells from normal cells are the increased proliferation and abnormal differentiation and maturation of these cells, which are due to regulatory changes in the emerging tumour. Normal cells use oxidative phosphorylation (OXPHOS) in the mitochondrion as a major source of energy during division. During OXPHOS, there are 36 ATP molecules produced from one molecule of glucose, in contrast to glycolysis which provides an ATP supply of only two molecules. Although aerobic glucose metabolism is more efficient, metabolism based on intensive glycolysis provides intermediate metabolites necessary for the synthesis of nucleic acids, proteins and lipids, which are in constant high demand due to the intense cell division in cancer. This is the main reason why the cancer cell does not “give up” on glycolysis despite the high demand for energy in the form of ATP. One of the evolving trends in the development of anti-cancer therapies is to exploit differences in the metabolism of normal cells and cancer cells. Currently constructed therapies, based on cell metabolism, focus on the attempt to reprogram the metabolic pathways of the cell in such a manner that it becomes possible to stop unrestrained proliferation. Full article

(This article belongs to the Special Issue Cancer Cell Metabolism)

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19 pages, 13594 KiB

Open AccessReview

Understanding the Central Role of Citrate in the Metabolism of Cancer Cells and Tumors: An Update

by Philippe Icard, Antoine Coquerel, Zherui Wu, Joseph Gligorov, David Fuks, Ludovic Fournel, Hubert Lincet and Luca Simula

Int. J. Mol. Sci. 2021, 22(12), 6587; https://doi.org/10.3390/ijms22126587 - 19 Jun 2021

Cited by 73 | Viewed by 9281

Abstract

Citrate plays a central role in cancer cells’ metabolism and regulation. Derived from mitochondrial synthesis and/or carboxylation of α-ketoglutarate, it is cleaved by ATP-citrate lyase into acetyl-CoA and oxaloacetate. The rapid turnover of these molecules in proliferative cancer cells maintains a low-level of citrate, precluding its retro-inhibition on glycolytic enzymes. In cancer cells relying on glycolysis, this regulation helps sustain the Warburg effect. In those relying on an oxidative metabolism, fatty acid β-oxidation sustains a high production of citrate, which is still rapidly converted into acetyl-CoA and oxaloacetate, this latter molecule sustaining nucleotide synthesis and gluconeogenesis. Therefore, citrate levels are rarely high in cancer cells. Resistance of cancer cells to targeted therapies, such as tyrosine kinase inhibitors (TKIs), is frequently sustained by aerobic glycolysis and its key oncogenic drivers, such as Ras and its downstream effectors MAPK/ERK and PI3K/Akt. Remarkably, in preclinical cancer models, the administration of high doses of citrate showed various anti-cancer effects, such as the inhibition of glycolysis, the promotion of cytotoxic drugs sensibility and apoptosis, the neutralization of extracellular acidity, and the inhibition of tumors growth and of key signalling pathways (in particular, the IGF-1R/AKT pathway). Therefore, these preclinical results support the testing of the citrate strategy in clinical trials to counteract key oncogenic drivers sustaining cancer development and resistance to anti-cancer therapies. Full article

(This article belongs to the Special Issue Cancer Cell Metabolism)

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16 pages, 1163 KiB

Open AccessReview

The Hidden Role of Hydrogen Sulfide Metabolism in Cancer

by Rong-Hsuan Wang, Yu-Hsin Chu and Kai-Ti Lin

Int. J. Mol. Sci. 2021, 22(12), 6562; https://doi.org/10.3390/ijms22126562 - 18 Jun 2021

Cited by 51 | Viewed by 6428

Abstract

Hydrogen Sulfide (H₂S), an endogenously produced gasotransmitter, is involved in various important physiological and disease conditions, including vasodilation, stimulation of cellular bioenergetics, anti-inflammation, and pro-angiogenesis. In cancer, aberrant up-regulation of H₂S-producing enzymes is frequently observed in different cancer types. The recognition that tumor-derived H₂S plays various roles during cancer development reveals opportunities to target H₂S-mediated signaling pathways in cancer therapy. In this review, we will focus on the mechanism of H₂S-mediated protein persulfidation and the detailed information about the dysregulation of H₂S-producing enzymes and metabolism in different cancer types. We will also provide an update on mechanisms of H₂S-mediated cancer progression and summarize current options to modulate H₂S production for cancer therapy. Full article

(This article belongs to the Special Issue Cancer Cell Metabolism)

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41 pages, 1266 KiB

Open AccessReview

Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer

by Aldona Kasprzak

Int. J. Mol. Sci. 2021, 22(12), 6434; https://doi.org/10.3390/ijms22126434 - 16 Jun 2021

Cited by 96 | Viewed by 18166

Abstract

Colorectal cancer (CRC) is one of the most common aggressive carcinoma types worldwide, characterized by unfavorable curative effect and poor prognosis. Epidemiological data re-vealed that CRC risk is increased in patients with metabolic syndrome (MetS) and its serum components (e.g., hyperglycemia). High glycemic index diets, which chronically raise post-prandial blood glucose, may at least in part increase colon cancer risk via the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. However, the underlying mechanisms linking IGF-1 and MetS are still poorly understood. Hyperactivated glucose uptake and aerobic glycolysis (the Warburg effect) are considered as a one of six hallmarks of cancer, including CRC. However, the role of insulin/IGF-1 signaling during the acquisition of the Warburg metabolic phenotypes by CRC cells is still poorly understood. It most likely results from the interaction of multiple processes, directly or indirectly regulated by IGF-1, such as activation of PI3K/Akt/mTORC, and Raf/MAPK signaling pathways, activation of glucose transporters (e.g., GLUT1), activation of key glycolytic enzymes (e.g., LDHA, LDH5, HK II, and PFKFB3), aberrant expression of the oncogenes (e.g., MYC, and KRAS) and/or overexpression of signaling proteins (e.g., HIF-1, TGF-β1, PI3K, ERK, Akt, and mTOR). This review describes the role of IGF-1 in glucose metabolism in physiology and colorectal carcinogenesis, including the role of the insulin/IGF system in the Warburg effect. Furthermore, current therapeutic strategies aimed at repairing impaired glucose metabolism in CRC are indicated. Full article

(This article belongs to the Special Issue Cancer Cell Metabolism)

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20 pages, 1416 KiB

Open AccessReview

Cancer Cell Metabolism in Hypoxia: Role of HIF-1 as Key Regulator and Therapeutic Target

by Vittoria Infantino, Anna Santarsiero, Paolo Convertini, Simona Todisco and Vito Iacobazzi

Int. J. Mol. Sci. 2021, 22(11), 5703; https://doi.org/10.3390/ijms22115703 - 27 May 2021

Cited by 209 | Viewed by 19077

Abstract

In order to meet the high energy demand, a metabolic reprogramming occurs in cancer cells. Its role is crucial in promoting tumor survival. Among the substrates in demand, oxygen is fundamental for bioenergetics. Nevertheless, tumor microenvironment is frequently characterized by low-oxygen conditions. Hypoxia-inducible factor 1 (HIF-1) is a pivotal modulator of the metabolic reprogramming which takes place in hypoxic cancer cells. In the hub of cellular bioenergetics, mitochondria are key players in regulating cellular energy. Therefore, a close crosstalk between mitochondria and HIF-1 underlies the metabolic and functional changes of cancer cells. Noteworthy, HIF-1 represents a promising target for novel cancer therapeutics. In this review, we summarize the molecular mechanisms underlying the interplay between HIF-1 and energetic metabolism, with a focus on mitochondria, of hypoxic cancer cells. Full article

(This article belongs to the Special Issue Cancer Cell Metabolism)

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