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Cancer Metabolism: Molecular Targeting and Implications for Therapy

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

Deadline for manuscript submissions: closed (20 March 2023) | Viewed by 16470

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Dr. Bal Krishna Chaube

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Guest Editor

Vascular Biology & Therapeutics Section, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
Interests: cancer metabolism; miRNA; metabolic disorder; cardiovascular biology; endothelial biology; exosome biology
Special Issues, Collections and Topics in MDPI journals

Dr. Shivendra Vikram Singh

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Guest Editor

Lead Researcher, Surgery Department, St Jude Children’s Research Hospital, Memphis, TN 38105, USA
Interests: cancer metabolism; immune cell metabolism; tumor microenvironment

Special Issue Information

Dear Colleagues,

Cancer cells have unique metabolic necessities that differ from most normal, non-proliferating cells. Cancer cells divert a considerable amount of carbon flux to glycolysis, even in the presence of abundant oxygen, a phenomenon famously known as the Warburg effect. The altered metabolism of cancer cells has been identified as one of the hallmarks of cancer. The ability of cancer cells to adapt in the extreme and changing tumor microenvironment provides them with survival and proliferation advantages. Altered metabolism in cancer cells can be associated with mitochondrial dysfunction, which involves inhibition of oxidative phosphorylation and, consequently, an increase in reactive oxygen species (ROS), and altered redox homeostasis leads to uncontrolled growth and proliferation. Depending upon the tissue of origin, local environment, and genetic factors, the metabolic phenotype of each cancer type may vary. A central unanswered question is how these factors influence the metabolic alteration in specific cancers to support growth and proliferation.

In recent years, targeting cancer metabolism has been identified as one of the most promising aspects of cancer therapeutics. There are numerous studies which suggest that targeting metabolic pathways reduces tumor progression. Therefore, it is crucial to understand how cancer cells adapt and reprogram their metabolism to overcomplete surrounding normal cells to gain proliferation and survival advantages. This can help to find new therapeutic targets to selectively control cancer cell growth and proliferation. We invite articles related to the field of cellular or systemic cancer metabolism, including glucose, fatty acid, and amino acid metabolism, as well as other related areas such as redox homeostasis, signaling pathways regulating cancer metabolism, obesity and cancer, tumor–immune interaction, and immune metabolism in the tumor microenvironment, and method articles such as metabolic flux analysis or any new and advanced method to study metabolism in cancer cells, drugs targeting cancer, and immune metabolism, for submission to this Special Issue.

Dr. Bal Krishna Chaube
Dr. Shivendra Vikram Singh
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.

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Keywords

cancer metabolism
Warburg effect
immuno-metabolism
mitochondria
bioenergetics
obesity and cancer
ROS
glucose metabolism
lipid metabolism
redox homeostasis
calorie restriction
metabolism and metastasis

Published Papers (7 papers)

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Research

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17 pages, 2531 KiB

Open AccessArticle

Serum NMR-Based Metabolomics Profiling Identifies Lipoprotein Subfraction Variables and Amino Acid Reshuffling in Myeloma Development and Progression

by Shona Pedersen, Morten Faarbæk Mikkelstrup, Søren Risom Kristensen, Najeha Rizwana Anwardeen, Mohamed A. Elrayess and Trygve Andreassen

Int. J. Mol. Sci. 2023, 24(15), 12275; https://doi.org/10.3390/ijms241512275 - 31 Jul 2023

Cited by 1 | Viewed by 1049

Abstract

Multiple myeloma (MM) is an incurable hematological cancer. It is preceded by monoclonal gammopathy of uncertain significance (MGUS)—an asymptomatic phase. It has been demonstrated that early detection increases the 5-year survival rate. However, blood-based biomarkers that enable early disease detection are lacking. Metabolomic and lipoprotein subfraction variable profiling is gaining traction to expand our understanding of disease states and, more specifically, for identifying diagnostic markers in patients with hematological cancers. This study aims to enhance our understanding of multiple myeloma (MM) and identify candidate metabolites, allowing for a more effective preventative treatment. Serum was collected from 25 healthy controls, 20 patients with MGUS, and 30 patients with MM. ¹H-NMR (Nuclear Magnetic Resonance) spectroscopy was utilized to evaluate serum samples. The metabolite concentrations were examined using multivariate, univariate, and pathway analysis. Metabolic profiles of the MGUS patients revealed lower levels of alanine, lysine, leucine but higher levels of formic acid when compared to controls. However, metabolic profiling of MM patients, compared to controls, exhibited decreased levels of total Apolipoprotein-A1, HDL-4 Apolipoprotein-A1, HDL-4 Apolipoprotein-A2, HDL Free Cholesterol, HDL-3 Cholesterol and HDL-4 Cholesterol. Lastly, metabolic comparison between MGUS to MM patients primarily indicated alterations in lipoproteins levels: Total Cholesterol, HDL Cholesterol, HDL Free Cholesterol, Total Apolipoprotein-A1, HDL Apolipoprotein-A1, HDL-4 Apolipoprotein-A1 and HDL-4 Phospholipids. This study provides novel insights into the serum metabolic and lipoprotein subfraction changes in patients as they progress from a healthy state to MGUS to MM, which may allow for earlier clinical detection and treatment. Full article

(This article belongs to the Special Issue Cancer Metabolism: Molecular Targeting and Implications for Therapy)

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20 pages, 2083 KiB

Open AccessArticle

Biological Activities of Miracle Berry Supercritical Extracts as Metabolic Regulators in Chronic Diseases

by Sonia Wagner, Marta Gómez de Cedrón, Joaquín Navarro del Hierro, Diego Martín-Hernández, María de las Nieves Siles, Susana Santoyo, Laura Jaime, Diana Martín, Tiziana Fornari and Ana Ramírez de Molina

Int. J. Mol. Sci. 2023, 24(8), 6957; https://doi.org/10.3390/ijms24086957 - 9 Apr 2023

Viewed by 2089

Abstract

Synsepalum dulcificum (Richardella dulcifica) is a berry fruit from West Africa with the ability to convert the sour taste into a sweet taste, and for this reason, the fruit is also known as the “miracle berry” (MB). The red and bright berry is rich in terpenoids. The fruit’s pulp and skin contain mainly phenolic compounds and flavonoids, which correlate with their antioxidant activity. Different polar extracts have been described to inhibit cell proliferation and transformation of cancer cell lines in vitro. In addition, MB has been shown to ameliorate insulin resistance in a preclinical model of diabetes induced by a chow diet enriched in fructose. Herein, we have compared the biological activities of three supercritical extracts obtained from the seed—a subproduct of the fruit—and one supercritical extract obtained from the pulp and the skin of MB. The four extracts have been characterized in terms of total polyphenols content. Moreover, the antioxidant, anti-inflammatory, hypo-lipidemic, and inhibition of colorectal cancer cell bioenergetics have been compared. Non-polar supercritical extracts from the seed are the ones with the highest effects on the inhibition of bioenergetic of colorectal (CRC) cancer cells. At the molecular level, the effects on cell bioenergetics seems to be related to the inhibition of main drivers of the de novo lipogenesis, such as the sterol regulatory element binding transcription factor (SREBF1) and downstream molecular targets fatty acid synthase (FASN) and stearoyl coenzyme desaturase 1 (SCD1). As metabolic reprograming is considered as one of the hallmarks of cancer, natural extracts from plants may provide complementary approaches in the treatment of cancer. Herein, for the first time, supercritical extracts from MB have been obtained, where the seed, a by-product of the fruit, seems to be rich in antitumor bioactive compounds. Based on these results, supercritical extracts from the seed merit further research to be proposed as co-adjuvants in the treatment of cancer. Full article

(This article belongs to the Special Issue Cancer Metabolism: Molecular Targeting and Implications for Therapy)

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17 pages, 9212 KiB

Open AccessArticle

Homotypic Entosis as a Potential Novel Diagnostic Marker in Breast Cancer

by Ireneusz Dziuba, Agata M. Gawel, Paweł Tyrna, Jędrzej Machtyl, Monika Olszanecka, Andrzej Pawlik, Cezary Wójcik, Lukasz P. Bialy and Izabela Mlynarczuk-Bialy

Int. J. Mol. Sci. 2023, 24(7), 6819; https://doi.org/10.3390/ijms24076819 - 6 Apr 2023

Cited by 5 | Viewed by 2115

Abstract

Homotypic entotic figures, which are a form of “cell-in-cell” structures, are considered a potential novel independent prognostic marker in various cancers. Nevertheless, the knowledge concerning the biological role of this phenomenon is still unclear. Since breast cancer cells are remarkably entosis-competent, we aimed to investigate and compare the frequency of entoses in a primary breast tumor and in its lymph node metastasis. Moreover, as there are limited data on defined molecular markers of entosis, we investigated entosis in correlation with classical breast cancer biomarkers used in routine pathomorphological diagnostics (HER2, ER, PR, and Ki67). In the study, a cohort of entosis-positive breast cancer samples paired into primary lesions and lymph node metastases was used. The inclusion criteria were a diagnosis of NOS cancer, lymph node metastases, the presence of entotic figures in the primary lesion, and/or lymph node metastases. In a selected, double-negative, HER2-positive NOS breast cancer case, entoses were characterized by a correlation between an epithelial–mesenchymal transition and proliferation markers. We observed that in the investigated cohort entotic figures were positively correlated with Ki67 and HER2, but not with ER or PR markers. Moreover, for the first time, we identified Ki67-positive mitotic inner entotic cells in clinical carcinoma samples. Our study performed on primary and secondary breast cancer specimens indicated that entotic figures, when examined by routine HE histological staining, present potential diagnostic value, since they correlate with two classical prognostic factors of breast cancer. Full article

(This article belongs to the Special Issue Cancer Metabolism: Molecular Targeting and Implications for Therapy)

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15 pages, 5705 KiB

Open AccessArticle

Lactate Rewrites the Metabolic Reprogramming of Uveal Melanoma Cells and Induces Quiescence Phenotype

by Lucia Longhitano, Sebastiano Giallongo, Laura Orlando, Giuseppe Broggi, Antonio Longo, Andrea Russo, Rosario Caltabiano, Cesarina Giallongo, Ignazio Barbagallo, Michelino Di Rosa, Rosario Giuffrida, Rosalba Parenti, Giovanni Li Volti, Nunzio Vicario and Daniele Tibullo

Int. J. Mol. Sci. 2023, 24(1), 24; https://doi.org/10.3390/ijms24010024 - 20 Dec 2022

Cited by 6 | Viewed by 2173

Abstract

Uveal melanoma (UM), the most common primary intraocular cancer in adults, is among the tumors with poorer prognosis. Recently, the role of the oncometabolite lactate has become attractive due to its role as hydroxycarboxylic acid receptor 1 (HCAR1) activator, as an epigenetic modulator inducing lysine residues lactylation and, of course, as a glycolysis end-product, bridging the gap between glycolysis and oxidative phosphorylation. The aim of the present study was to dissect in UM cell line (92.1) the role of lactate as either a metabolite or a signaling molecule, using the known modulators of HCAR1 and of lactate transporters. Our results show that lactate (20 mM) resulted in a significant decrease in cell proliferation and migration, acting and switching cell metabolism toward oxidative phosphorylation. These results were coupled with increased euchromatin content and quiescence in UM cells. We further showed, in a clinical setting, that an increase in lactate transporters MCT4 and HCAR1 is associated with a spindle-shape histological type in UM. In conclusion, our results suggest that lactate metabolism may serve as a prognostic marker of UM progression and may be exploited as a potential therapeutic target. Full article

(This article belongs to the Special Issue Cancer Metabolism: Molecular Targeting and Implications for Therapy)

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13 pages, 4127 KiB

Open AccessArticle

Lipid Droplets in Lung Cancers Are Crucial for the Cell Growth and Starvation Survival

by Jrhau Lung, Ming-Szu Hung, Ting-Yao Wang, Kuan-Liang Chen, Chi-Wen Luo, Yuan-Yuan Jiang, Shin-Yi Wu, Li-Wen Lee, Paul-Yann Lin, Fen-Fen Chen, Hui-Fen Liao and Yu-Ching Lin

Int. J. Mol. Sci. 2022, 23(20), 12533; https://doi.org/10.3390/ijms232012533 - 19 Oct 2022

Cited by 8 | Viewed by 2434

Abstract

For rapid and unlimited cell growth and proliferation, cancer cells require large quantities of nutrients. Many metabolic pathways and nutrient uptake systems are frequently reprogrammed and upregulated to meet the demand from cancer cells, including the demand for lipids. The lipids for most adult normal cells are mainly acquired from the circulatory system. Whether different cancer cells adopt identical mechanisms to ensure sufficient lipid supply, and whether the lipid demand and supply meet each other, remains unclear, and was investigated in lung cancer cells. Results showed that, despite frequent upregulation in de novo lipogenesis and the lipid transporter system, different lung cancer cells adopt different proteins to acquire sufficient lipids, and the lipid supply frequently exceeds the demand, as significant amounts of lipids stored in the lipid droplets could be found within lung cancer cells. Lipid droplet surface protein, PLIN3, was found frequently overexpressed since the early stage in lung cancer tissues. Although the expression is not significantly associated with a specific gender, age, histology type, disease stage, and smoking habit, the frequently elevated expression of PLIN3 protein indicates the importance of lipid droplets for lung cancer. These lipid droplets are not only for nutrient storage, but are also crucial for tumor growth and proliferation, as well as survival in starvation. These results suggest that manipulation of lipid droplet formation or TG storage in lung cancer cells could potentially decrease the progression of lung cancer. Further exploration of lipid biology in lung cancer could help design novel treatment strategies. Full article

(This article belongs to the Special Issue Cancer Metabolism: Molecular Targeting and Implications for Therapy)

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18 pages, 5361 KiB

Open AccessArticle

Suppression of Ribose-5-Phosphate Isomerase a Induces ROS to Activate Autophagy, Apoptosis, and Cellular Senescence in Lung Cancer

by Yu-Chin Nieh, Yu-Ting Chou, Yu-Ting Chou, Chao-Yung Wang, Shi-Xian Lin, Shih-Ci Ciou, Chiou-Hwa Yuh and Horng-Dar Wang

Int. J. Mol. Sci. 2022, 23(14), 7883; https://doi.org/10.3390/ijms23147883 - 17 Jul 2022

Cited by 5 | Viewed by 2274

Abstract

Ribose-5-phosphate isomerase A (RPIA) regulates tumorigenesis in liver and colorectal cancer. However, the role of RPIA in lung cancer remains obscure. Here we report that the suppression of RPIA diminishes cellular proliferation and activates autophagy, apoptosis, and cellular senescence in lung cancer cells. First, we detected that RPIA protein was increased in the human lung cancer versus adjust normal tissue via tissue array. Next, the knockdown of RPIA in lung cancer cells displayed autophagic vacuoles, enhanced acridine orange staining, GFP-LC3 punctae, accumulated autophagosomes, and showed elevated levels of LC3-II and reduced levels of p62, together suggesting that the suppression of RPIA stimulates autophagy in lung cancer cells. In addition, decreased RPIA expression induced apoptosis by increasing levels of Bax, cleaved PARP and caspase-3 and apoptotic cells. Moreover, RPIA knockdown triggered cellular senescence and increased p53 and p21 levels in lung cancer cells. Importantly, RPIA knockdown elevated reactive oxygen species (ROS) levels. Treatment of ROS scavenger N-acetyl-L-cysteine (NAC) reverts the activation of autophagy, apoptosis and cellular senescence by RPIA knockdown in lung cancer cells. In conclusion, RPIA knockdown induces ROS levels to activate autophagy, apoptosis, and cellular senescence in lung cancer cells. Our study sheds new light on RPIA suppression in lung cancer therapy. Full article

(This article belongs to the Special Issue Cancer Metabolism: Molecular Targeting and Implications for Therapy)

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Review

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35 pages, 3127 KiB

Open AccessReview

Glioblastoma Metabolism: Insights and Therapeutic Strategies

by Chloé Bernhard, Damien Reita, Sophie Martin, Natacha Entz-Werle and Monique Dontenwill

Int. J. Mol. Sci. 2023, 24(11), 9137; https://doi.org/10.3390/ijms24119137 - 23 May 2023

Cited by 6 | Viewed by 3576

Abstract

Tumor metabolism is emerging as a potential target for cancer therapies. This new approach holds particular promise for the treatment of glioblastoma, a highly lethal brain tumor that is resistant to conventional treatments, for which improving therapeutic strategies is a major challenge. The presence of glioma stem cells is a critical factor in therapy resistance, thus making it essential to eliminate these cells for the long-term survival of cancer patients. Recent advancements in our understanding of cancer metabolism have shown that glioblastoma metabolism is highly heterogeneous, and that cancer stem cells exhibit specific metabolic traits that support their unique functionality. The objective of this review is to examine the metabolic changes in glioblastoma and investigate the role of specific metabolic processes in tumorigenesis, as well as associated therapeutic approaches, with a particular focus on glioma stem cell populations. Full article

(This article belongs to the Special Issue Cancer Metabolism: Molecular Targeting and Implications for Therapy)

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