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Targeting Tumor Metabolism: From Mechanisms to Therapies

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (31 August 2020) | Viewed by 71258

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Dr. Iola F. Duarte Ciceco

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Department of Chemistry, Technological Laboratories, CICECO - Aveiro Institute of Materials, University of Aveiro, 3810-093 Aveiro, Portugal
Interests: toxicity and biological assessment of (nano)materials with biomedical applications; metabolism of immune cells and metabolic immunomodulation; metabolism of tumor cells and metabolic effects of anticancer therapies (drugs, nanomedicines, photothermal therapy); NMR spectroscopy and metabolomics
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Prof.Dr. Ana M. Gil

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Department of Chemistry, Technological Laboratories, CICECO - Aveiro Institute of Materials, University of Aveiro, 3810-093 Aveiro, Portugal
Interests: metabolomics of human biofluids, tissues, and cellular systems for the biochemical characterisation of diseases (mainly prenatal/newborn disorders and cancer); metabolomics testing of bio- and/or nano-materials for assessment of in vitro and in vivo biological performance; metabolomic assessment of environmental effects on human metabolism; metabolomics for the routine quality control of products and processes in the food industry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

With the support of advanced molecular and analytical tools, our understanding of tumor metabolism has grown immensely over the past years. The intricate relationship between oncogenic events and metabolic reprogramming is currently recognized as an important cancer hallmark, which actively supports the proliferation, survival, and migration of tumor cells. Different metabolic features such as elevated glucose uptake and glycolysis, enhanced synthesis of nucleotides and lipids, or an altered redox status have been identified across several cellular and animal models, as well as in human samples. Various metabolites have been proposed as disease biomarkers with potential diagnostic or prognostic value, and a renewed interest in exploring metabolic targets for therapeutic purposes has arisen. At the same time, a number of important questions have emerged, for instance, regarding the metabolic diversity between tumor types and their histological/molecular subtypes, the metabolic crosstalk between tumor cells and other cells in the tumor microenvironment (such as immune cells, adipocytes, and fibroblasts), or the translatability of the in vitro findings to in vivo situations.

For this Special Issue, we would like to invite review papers or original research articles that address the topic of tumor metabolism and the above-mentioned questions. In particular, studies that contribute to advancing the current mechanistic understanding of cancer metabolic rewiring, as well as manuscripts providing novel application-oriented perspectives, are highly welcome.

We look forward to receiving your contributions.

Dr. Iola F. Duarte
Prof. Ana M. Gil
Guest Editors

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Keywords

tumor metabolism
metabolic pathways
‘omics’ approaches
metabolic targets and drugs
tumor microenvironment
metabolic biomarkers

Related Special Issue

Targeting Tumor Metabolism: From Mechanisms to Therapies II in Biomolecules (8 articles)

Published Papers (12 papers)

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Research

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16 pages, 3597 KiB

Open AccessFeature PaperArticle

Differential Expression of ADP/ATP Carriers as a Biomarker of Metabolic Remodeling and Survival in Kidney Cancers

by Lucia Trisolini, Luna Laera, Maria Favia, Antonella Muscella, Alessandra Castegna, Vito Pesce, Lorenzo Guerra, Anna De Grassi, Mariateresa Volpicella and Ciro Leonardo Pierri

Biomolecules 2021, 11(1), 38; https://doi.org/10.3390/biom11010038 - 30 Dec 2020

Cited by 11 | Viewed by 3474

Abstract

ADP/ATP carriers (AACs) are mitochondrial transport proteins playing a strategic role in maintaining the respiratory chain activity, fueling the cell with ATP, and also regulating mitochondrial apoptosis. To understand if AACs might represent a new molecular target for cancer treatment, we evaluated AAC expression levels in cancer/normal tissue pairs available on the Tissue Cancer Genome Atlas database (TCGA), observing that AACs are dysregulated in most of the available samples. It was observed that at least two AACs showed a significant differential expression in all the available kidney cancer/normal tissue pairs. Thus, we investigated AAC expression in the corresponding kidney non-cancer (HK2)/cancer (RCC-Shaw and CaKi-1) cell lines, grown in complete medium or serum starvation, for investigating how metabolic alteration induced by different growth conditions might influence AAC expression and resistance to mitochondrial apoptosis initiators, such as “staurosporine” or the AAC highly selective inhibitor “carboxyatractyloside”. Our analyses showed that AAC2 and AAC3 transcripts are more expressed than AAC1 in all the investigated kidney cell lines grown in complete medium, whereas serum starvation causes an increase of at least two AAC transcripts in kidney cancer cell lines compared to non-cancer cells. However, the total AAC protein content is decreased in the investigated cancer cell lines, above all in the serum-free medium. The observed decrease in AAC protein content might be responsible for the decrease of OXPHOS activity and for the observed lowered sensitivity to mitochondrial apoptosis induced by staurosporine or carboxyatractyloside. Notably, the cumulative probability of the survival of kidney cancer patients seriously decreases with the decrease of AAC1 expression in KIRC and KIRP tissues making AAC1 a possible new biomarker of metabolic remodeling and survival in kidney cancers. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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18 pages, 2801 KiB

Open AccessArticle

Targeting Mitochondria in Melanoma

by Sepideh Aminzadeh-Gohari, Daniela D. Weber, Luca Catalano, René G. Feichtinger, Barbara Kofler and Roland Lang

Biomolecules 2020, 10(10), 1395; https://doi.org/10.3390/biom10101395 - 30 Sep 2020

Cited by 25 | Viewed by 4054

Abstract

Drastically elevated glycolytic activity is a prominent metabolic feature of cancer cells. Until recently it was thought that tumor cells shift their entire energy production from oxidative phosphorylation (OXPHOS) to glycolysis. However, new evidence indicates that many cancer cells still have functional OXPHOS, despite their increased reliance on glycolysis. Growing pre-clinical and clinical evidence suggests that targeting mitochondrial metabolism has anti-cancer effects. Here, we analyzed mitochondrial respiration and the amount and activity of OXPHOS complexes in four melanoma cell lines and normal human dermal fibroblasts (HDFs) by Seahorse real-time cell metabolic analysis, immunoblotting, and spectrophotometry. We also tested three clinically approved antibiotics, one anti-parasitic drug (pyrvinium pamoate), and a novel anti-cancer agent (ONC212) for effects on mitochondrial respiration and proliferation of melanoma cells and HDFs. We found that three of the four melanoma cell lines have elevated glycolysis as well as OXPHOS, but contain dysfunctional mitochondria. The antibiotics produced different effects on the melanoma cells and HDFs. The anti-parasitic drug strongly inhibited respiration and proliferation of both the melanoma cells and HDFs. ONC212 reduced respiration in melanoma cells and HDFs, and inhibited the proliferation of melanoma cells. Our findings highlight ONC212 as a promising drug for targeting mitochondrial respiration in cancer. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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19 pages, 2737 KiB

Open AccessArticle

Hormone-Independent Mouse Mammary Adenocarcinomas with Different Metastatic Potential Exhibit Different Metabolic Signatures

by Daniela Bispo, Victoria Fabris, Caroline A. Lamb, Claudia Lanari, Luisa A. Helguero and Ana M. Gil

Biomolecules 2020, 10(9), 1242; https://doi.org/10.3390/biom10091242 - 27 Aug 2020

Cited by 2 | Viewed by 2306

Abstract

The metabolic characteristics of metastatic and non-metastatic breast carcinomas remain poorly studied. In this work, untargeted Nuclear Magnetic Resonance (NMR) metabolomics was used to compare two medroxyprogesterone acetate (MPA)-induced mammary carcinomas lines with different metastatic abilities. Different metabolic signatures distinguished the non-metastatic (59-2-HI) and the metastatic (C7-2-HI) lines, with glucose, amino acid metabolism, nucleotide metabolism and lipid metabolism as the major affected pathways. Non-metastatic tumours appeared to be characterised by: (a) reduced glycolysis and tricarboxylic acid cycle (TCA) activities, possibly resulting in slower NADH biosynthesis and reduced mitochondrial transport chain activity and ATP synthesis; (b) glutamate accumulation possibly related to reduced glutathione activity and reduced mTORC1 activity; and (c) a clear shift to lower phosphoscholine/glycerophosphocholine ratios and sphingomyelin levels. Within each tumour line, metabolic profiles also differed significantly between tumours (i.e., mice). Metastatic tumours exhibited marked inter-tumour changes in polar compounds, some suggesting different glycolytic capacities. Such tumours also showed larger intra-tumour variations in metabolites involved in nucleotide and cholesterol/fatty acid metabolism, in tandem with less changes in TCA and phospholipid metabolism, compared to non-metastatic tumours. This study shows the valuable contribution of untargeted NMR metabolomics to characterise tumour metabolism, thus opening enticing opportunities to find metabolic markers related to metastatic ability in endocrine breast cancer. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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18 pages, 3423 KiB

Open AccessArticle

Triple Negative Breast Cancer and Breast Epithelial Cells Differentially Reprogram Glucose and Lipid Metabolism upon Treatment with Triterpenic Acids

by Ângela R. Guerra, Ana F. Paulino, Maria M. Castro, Helena Oliveira, Maria F. Duarte and Iola F. Duarte

Biomolecules 2020, 10(8), 1163; https://doi.org/10.3390/biom10081163 - 08 Aug 2020

Cited by 9 | Viewed by 3576

Abstract

Plant-derived pentacyclic triterpenic acids (TAs) have gained increasing attention due to their multiple biological activities. Betulinic acid (BA) and ursolic acid (UA) modulate diverse pathways in carcinogenesis, offering increased changes of success in refractory cancers, such as triple negative breast cancer (TNBC). The present work aimed to assess the metabolic effects of BA and UA in MDA-MB-231 breast cancer cells (TNBC model), as well as in MCF-10A non-cancer breast epithelial cells, with a view to unveiling the involvement of metabolic reprogramming in cellular responses to these TAs. Cell viability and cell cycle analyses were followed by assessment of changes in the cells exo- and endometabolome through ¹H NMR analysis of cell culture medium supernatants, aqueous and organic cell extracts. In MDA-MB-231 cells, BA was suggested to induce a transient upregulation of glucose consumption and glycolytic conversion, tricarboxylic acid (TCA) cycle intensification, and hydrolysis of neutral lipids, while UA effects were much less pronounced. In MCF-10A cells, boosting of glucose metabolism by the two TAs was accompanied by diversion of glycolytic intermediates to the hexosamine biosynthetic pathway (HBP) and the synthesis of neutral lipids, possibly stored in detoxifying lipid droplets. Additionally, breast epithelial cells intensified pyruvate consumption and TCA cycle activity, possibly to compensate for oxidative impairment of pyruvate glycolytic production. This study provided novel insights into the metabolic effects of BA and UA in cancer and non-cancer breast cells, thus improving current understanding of the action of these compounds at the molecular level. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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17 pages, 2703 KiB

Open AccessArticle

Large-Scale Differential Gene Expression Transcriptomic Analysis Identifies a Metabolic Signature Shared by All Cancer Cells

by Areej Abu Rmaileh, Balakrishnan Solaimuthu, Mayur Tanna, Anees Khatib, Michal Ben Yosef, Arata Hayashi, Michal Lichtenstein and Yoav D. Shaul

Biomolecules 2020, 10(5), 701; https://doi.org/10.3390/biom10050701 - 30 Apr 2020

Cited by 3 | Viewed by 3515

Abstract

Cancer-dependent metabolic rewiring is often manifested by selective expression of enzymes essential for the transformed cells’ viability. However, the metabolic variations between normal and transformed cells are not fully characterized, and therefore, a systematic analysis will result in the identification of unknown cellular mechanisms crucial for tumorigenesis. Here, we applied differential gene expression transcriptome analysis to examine the changes in metabolic gene profiles between a wide range of normal tissues and cancer samples. We found that, in contrast to normal tissues which exhibit a tissue-specific expression profile, cancer samples are more homogenous despite their diverse origins. This similarity is due to a “proliferation metabolic signature” (PMS), composed of 158 genes (87 upregulated and 71 downregulated gene sets), where 143 are common to all proliferative cells but 15 are cancer specific. Intriguingly, the PMS gene set is enriched for genes encoding rate-limiting enzymes, and its upregulated set with genes associated with poor patient outcome and essential genes. Among these essential genes is ribulose-5-phosphate-3-epimerase (RPE), which encodes a pentose phosphate pathway enzyme and whose role in cancer is still unclear. Collectively, we identified a set of metabolic genes that can serve as novel cancer biomarkers and potential targets for drug development. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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21 pages, 4054 KiB

Open AccessArticle

Mitochondrial Functions, Energy Metabolism and Protein Glycosylation are Interconnected Processes Mediating Resistance to Bortezomib in Multiple Myeloma Cells

by Daniele Tibullo, Cesarina Giallongo, Alessandra Romano, Nunzio Vicario, Alessandro Barbato, Fabrizio Puglisi, Rosalba Parenti, Angela Maria Amorini, Miriam Wissam Saab, Barbara Tavazzi, Renata Mangione, Maria Violetta Brundo, Giacomo Lazzarino, Giuseppe Alberto Palumbo, Giovanni Li Volti, Francesco Di Raimondo and Giuseppe Lazzarino

Biomolecules 2020, 10(5), 696; https://doi.org/10.3390/biom10050696 - 30 Apr 2020

Cited by 41 | Viewed by 3792

Abstract

The proteasome inhibitor bortezomib (BTZ) has emerged as an effective drug for the treatment of multiple myeloma even though many patients relapse from BTZ therapy. The present study investigated the metabolic pathways underlying the acquisition of bortezomib resistance in multiple myeloma. We used two different clones of multiple myeloma cell lines exhibiting different sensitivities to BTZ (U266 and U266-R) and compared them in terms of metabolic profile, mitochondrial fitness and redox balance homeostasis capacity. Our results showed that the BTZ-resistant clone (U266-R) presented increased glycosylated UDP-derivatives when compared to BTZ-sensitive cells (U266), thus also suggesting higher activities of the hexosamine biosynthetic pathway (HBP), regulating not only protein O- and N-glycosylation but also mitochondrial functions. Notably, U266-R displayed increased mitochondrial biogenesis and mitochondrial dynamics associated with stronger antioxidant defenses. Furthermore, U266-R maintained a significantly higher concentration of substrates for protein glycosylation when compared to U266, particularly for UDP-GlcNac, thus further suggesting the importance of glycosylation in the BTZ pharmacological response. Moreover, BTZ-treated U266-R showed significantly higher ATP/ADP ratios and levels of ECP and also exhibited increased mitochondrial fitness and antioxidant response. In conclusions, our findings suggest that the HBP may play a major role in mitochondrial fitness, driving BTZ resistance in multiple myeloma and thus representing a possible target for new drug development for BTZ-resistant patients. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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Review

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28 pages, 3067 KiB

Open AccessEditor’s ChoiceReview

Role of Glutathione in Cancer: From Mechanisms to Therapies

by Luke Kennedy, Jagdeep K. Sandhu, Mary-Ellen Harper and Miroslava Cuperlovic-Culf

Biomolecules 2020, 10(10), 1429; https://doi.org/10.3390/biom10101429 - 09 Oct 2020

Cited by 363 | Viewed by 20425

Abstract

Glutathione (GSH) is the most abundant non-protein thiol present at millimolar concentrations in mammalian tissues. As an important intracellular antioxidant, it acts as a regulator of cellular redox state protecting cells from damage caused by lipid peroxides, reactive oxygen and nitrogen species, and xenobiotics. Recent studies have highlighted the importance of GSH in key signal transduction reactions as a controller of cell differentiation, proliferation, apoptosis, ferroptosis and immune function. Molecular changes in the GSH antioxidant system and disturbances in GSH homeostasis have been implicated in tumor initiation, progression, and treatment response. Hence, GSH has both protective and pathogenic roles. Although in healthy cells it is crucial for the removal and detoxification of carcinogens, elevated GSH levels in tumor cells are associated with tumor progression and increased resistance to chemotherapeutic drugs. Recently, several novel therapies have been developed to target the GSH antioxidant system in tumors as a means for increased response and decreased drug resistance. In this comprehensive review we explore mechanisms of GSH functionalities and different therapeutic approaches that either target GSH directly, indirectly or use GSH-based prodrugs. Consideration is also given to the computational methods used to describe GSH related processes for in silico testing of treatment effects. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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25 pages, 1320 KiB

Open AccessReview

Take Advantage of Glutamine Anaplerosis, the Kernel of the Metabolic Rewiring in Malignant Gliomas

by Filipa Martins, Luís G. Gonçalves, Marta Pojo and Jacinta Serpa

Biomolecules 2020, 10(10), 1370; https://doi.org/10.3390/biom10101370 - 26 Sep 2020

Cited by 12 | Viewed by 3693

Abstract

Glutamine is a non-essential amino acid that plays a key role in the metabolism of proliferating cells including neoplastic cells. In the central nervous system (CNS), glutamine metabolism is particularly relevant, because the glutamine-glutamate cycle is a way of controlling the production of glutamate-derived neurotransmitters by tightly regulating the bioavailability of the amino acids in a neuron-astrocyte metabolic symbiosis-dependent manner. Glutamine-related metabolic adjustments have been reported in several CNS malignancies including malignant gliomas that are considered ‘glutamine addicted’. In these tumors, glutamine becomes an essential amino acid preferentially used in energy and biomass production including glutathione (GSH) generation, which is crucial in oxidative stress control. Therefore, in this review, we will highlight the metabolic remodeling that gliomas undergo, focusing on glutamine metabolism. We will address some therapeutic regimens including novel research attempts to target glutamine metabolism and a brief update of diagnosis strategies that take advantage of this altered profile. A better understanding of malignant glioma cell metabolism will help in the identification of new molecular targets and the design of new therapies. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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28 pages, 6571 KiB

Open AccessReview

Heterogeneity of Glucose Transport in Lung Cancer

by Cesar A. Martinez and Claudio Scafoglio

Biomolecules 2020, 10(6), 868; https://doi.org/10.3390/biom10060868 - 05 Jun 2020

Cited by 17 | Viewed by 4006

Abstract

Increased glucose uptake is a known hallmark of cancer. Cancer cells need glucose for energy production via glycolysis and the tricarboxylic acid cycle, and also to fuel the pentose phosphate pathway, the serine biosynthetic pathway, lipogenesis, and the hexosamine pathway. For this reason, glucose transport inhibition is an emerging new treatment for different malignancies, including lung cancer. However, studies both in animal models and in humans have shown high levels of heterogeneity in the utilization of glucose and other metabolites in cancer, unveiling a complexity that is difficult to target therapeutically. Here, we present an overview of different levels of heterogeneity in glucose uptake and utilization in lung cancer, with diagnostic and therapeutic implications. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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15 pages, 1105 KiB

Open AccessEditor’s ChoiceReview

Methionine Dependence of Cancer

by Peter Kaiser

Biomolecules 2020, 10(4), 568; https://doi.org/10.3390/biom10040568 - 08 Apr 2020

Cited by 100 | Viewed by 9105

Abstract

Tumorigenesis is accompanied by the reprogramming of cellular metabolism. The shift from oxidative phosphorylation to predominantly glycolytic pathways to support rapid growth is well known and is often referred to as the Warburg effect. However, other metabolic changes and acquired needs that distinguish cancer cells from normal cells have also been discovered. The dependence of cancer cells on exogenous methionine is one of them and is known as methionine dependence or the Hoffman effect. This phenomenon describes the inability of cancer cells to proliferate when methionine is replaced with its metabolic precursor, homocysteine, while proliferation of non-tumor cells is unaffected by these conditions. Surprisingly, cancer cells can readily synthesize methionine from homocysteine, so their dependency on exogenous methionine reflects a general need for altered metabolic flux through pathways linked to methionine. In this review, an overview of the field will be provided and recent discoveries will be discussed. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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20 pages, 1499 KiB

Open AccessReview

A Sweet Connection? Fructose’s Role in Hepatocellular Carcinoma

by Brittany Dewdney, Alexandra Roberts, Liang Qiao, Jacob George and Lionel Hebbard

Biomolecules 2020, 10(4), 496; https://doi.org/10.3390/biom10040496 - 25 Mar 2020

Cited by 13 | Viewed by 5348

Abstract

Hepatocellular carcinoma is one of few cancer types that continues to grow in incidence and mortality worldwide. With the alarming increase in diabetes and obesity rates, the higher rates of hepatocellular carcinoma are a result of underlying non-alcoholic fatty liver disease. Many have attributed disease progression to an excess consumption of fructose sugar. Fructose has known toxic effects on the liver, including increased fatty acid production, increased oxidative stress, and insulin resistance. These effects have been linked to non-alcoholic fatty liver (NAFLD) disease and a progression to non-alcoholic steatohepatitis (NASH). While the literature suggests fructose may enhance liver cancer progression, the precise mechanisms in which fructose induces tumor formation remains largely unclear. In this review, we summarize the current understanding of fructose metabolism in liver disease and liver tumor development. Furthermore, we consider the latest knowledge of cancer cell metabolism and speculate on additional mechanisms of fructose metabolism in hepatocellular carcinoma. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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23 pages, 570 KiB

Open AccessReview

Modulation of Mitochondrial Metabolic Reprogramming and Oxidative Stress to Overcome Chemoresistance in Cancer

by Rosario Avolio, Danilo Swann Matassa, Daniela Criscuolo, Matteo Landriscina and Franca Esposito

Biomolecules 2020, 10(1), 135; https://doi.org/10.3390/biom10010135 - 14 Jan 2020

Cited by 43 | Viewed by 6904

Abstract

Metabolic reprogramming, carried out by cancer cells to rapidly adapt to stress such as hypoxia and limited nutrient conditions, is an emerging concepts in tumor biology, and is now recognized as one of the hallmarks of cancer. In contrast with conventional views, based on the classical Warburg effect, these metabolic alterations require fully functional mitochondria and finely-tuned regulations of their activity. In turn, the reciprocal regulation of the metabolic adaptations of cancer cells and the microenvironment critically influence disease progression and response to therapy. This is also realized through the function of specific stress-adaptive proteins, which are able to relieve oxidative stress, inhibit apoptosis, and facilitate the switch between metabolic pathways. Among these, the molecular chaperone tumor necrosis factor receptor associated protein 1 (TRAP1), the most abundant heat shock protein 90 (HSP90) family member in mitochondria, is particularly relevant because of its role as an oncogene or a tumor suppressor, depending on the metabolic features of the specific tumor. This review highlights the interplay between metabolic reprogramming and cancer progression, and the role of mitochondrial activity and oxidative stress in this setting, examining the possibility of targeting pathways of energy metabolism as a therapeutic strategy to overcome drug resistance, with particular emphasis on natural compounds and inhibitors of mitochondrial HSP90s. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies)

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