Metabolism and Cancer Biology

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Cell Metabolism".

Deadline for manuscript submissions: closed (15 December 2023) | Viewed by 4606

Special Issue Editor

Department of Molecular Biology and Biochemistry, University of California, Irvine, CA, USA
Interests: cancer metabolism and aging

Special Issue Information

Dear Colleagues,

Metabolic reprogramming has been recognized as one of the critical cancer hallmarks supporting tumor initiation and progression. Due to elevated glycolysis and glutaminolysis, increased uptake of amino acids and fatty acids, and dysfunctional tumor vascularization, cancer cells often face a metabolically limiting microenvironment. As a result, cells are forced to rewire their metabolism to support rapid proliferation, continuous growth, and survival in stress conditions. During the last decades, studies have revealed that the metabolic adaptations in cancer are caused by oncogene activation and mutant metabolic enzymes. In many cases, the effectors of oncogenes or suppressor genes carry out the enhancement of energetic and macromolecule biosynthesis and maintenance of homeostasis. Recent studies have also revealed various metabolic enzyme mutations that contribute directly to cancer progression, metastasis, and resistance to treatment. These distinguishing features of cancer metabolism have been extensively exploited for the improvement of cancer diagnosis, prognosis, tumor imaging, targeted therapies, and cancer recurrence detection. Therefore, having a better understanding of the mechanisms of altered cellular metabolism, the adaptation to the tumor microenvironment, as well as the metabolic crosstalk between cancer cells and other cell types will provide new insight into basic cancer biology and clinical patient care. This special issue on Metabolism and Cancer Biology will highlight the above issues. As such, we welcome submissions of research and review articles addressing the functions of metabolism on cancer in both basic and clinical research.

Dr. Ying Yang
Guest Editor

Manuscript Submission Information

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Keywords

  • cancer metabolism
  • metabolic reprogramming
  • tumor microenvironment
  • metabolic homeostasis
  • targeted therapy

Published Papers (4 papers)

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Research

15 pages, 2406 KiB  
Article
Assessing the Therapeutic Efficacy of Proton Transport Inhibitors in a Triple-Negative Breast Cancer Murine Model with Magnetic Resonance Imaging—Chemical Exchange Saturation Transfer Tumor pH Imaging
by Chetan Dhakan, Annasofia Anemone, Vittoria Ventura, Antonella Carella, Alessia Corrado, Elisa Pirotta, Daisy Villano, Feriel Romdhane, Francesco Gammaraccio, Silvio Aime and Dario Livio Longo
Metabolites 2023, 13(11), 1161; https://doi.org/10.3390/metabo13111161 - 18 Nov 2023
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Abstract
Proton transporters play a key role in maintaining the acidic tumor microenvironment; hence, their inhibition has been proposed as a new therapeutic treatment, although few methods can accurately assess their effect in vivo. In this study, we investigated whether MRI-CEST (Magnetic Resonance Imaging—Chemical [...] Read more.
Proton transporters play a key role in maintaining the acidic tumor microenvironment; hence, their inhibition has been proposed as a new therapeutic treatment, although few methods can accurately assess their effect in vivo. In this study, we investigated whether MRI-CEST (Magnetic Resonance Imaging—Chemical Exchange Saturation Transfer) tumor pH imaging can be a useful tool to evaluate in vivo the therapeutic efficacy of several Proton Pump Inhibitors (PPIs) in breast cancer. Cell viability and extracellular pH assays were carried out in breast cancer cells cultured at physiological pH (7.4) or acid-adapted (pH of 6.5 and 6.8) following the exposure to inhibitors of V-ATPase (Lansoprazole, Esomeprazole) or NHE1 (Amiloride, Cariporide) at several concentrations. Next, triple-negative breast cancer 4T1 tumor-bearing mice were treated with Lansoprazole or Amiloride and MRI-CEST tumor pH imaging was utilized to assess the in vivo efficacy. Only Lansoprazole induced, in addition to breast cancer cell toxicity, a significant inhibition of proton extrusion. A significant reduction in tumor volume, prolonged survival, and increase in extracellular tumor pH after 1 and 2 weeks were observed after Lansoprazole treatment, whereas no significant changes were detected upon Amiloride treatment. Our results suggested that MRI-CEST tumor pH imaging can monitor the therapeutic efficacy of PPIs in breast cancer murine models. Full article
(This article belongs to the Special Issue Metabolism and Cancer Biology)
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18 pages, 4191 KiB  
Article
Inhibition of GCN2 Reveals Synergy with Cell-Cycle Regulation and Proteostasis
by Gregory Gauthier-Coles, Farid Rahimi, Angelika Bröer and Stefan Bröer
Metabolites 2023, 13(10), 1064; https://doi.org/10.3390/metabo13101064 - 09 Oct 2023
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Abstract
The integrated stress response is a signaling network comprising four branches, each sensing different cellular stressors, converging on the phosphorylation of eIF2α to downregulate global translation and initiate recovery. One of these branches includes GCN2, which senses cellular amino acid insufficiency and participates [...] Read more.
The integrated stress response is a signaling network comprising four branches, each sensing different cellular stressors, converging on the phosphorylation of eIF2α to downregulate global translation and initiate recovery. One of these branches includes GCN2, which senses cellular amino acid insufficiency and participates in maintaining amino acid homeostasis. Previous studies have shown that GCN2 is a viable cancer target when amino acid stress is induced by inhibiting an additional target. In this light, we screened numerous drugs for their potential to synergize with the GCN2 inhibitor TAP20. The drug sensitivity of six cancer cell lines to a panel of 25 compounds was assessed. Each compound was then combined with TAP20 at concentrations below their IC50, and the impact on cell growth was evaluated. The strongly synergistic combinations were further characterized using synergy analyses and matrix-dependent invasion assays. Inhibitors of proteostasis and the MEK–ERK pathway, as well as the pan-CDK inhibitors, flavopiridol, and seliciclib, were potently synergistic with TAP20 in two cell lines. Among their common CDK targets was CDK7, which was more selectively targeted by THZ-1 and synergized with TAP20. Moreover, these combinations were partially synergistic when assessed using matrix-dependent invasion assays. However, TAP20 alone was sufficient to restrict invasion at concentrations well below its growth-inhibitory IC50. We conclude that GCN2 inhibition can be further explored in vivo as a cancer target. Full article
(This article belongs to the Special Issue Metabolism and Cancer Biology)
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13 pages, 2279 KiB  
Article
Vitamin D and Its Metabolites Status before and during Chemotherapy in Caucasian Breast Cancer Patients
by Małgorzata Kimsa-Furdzik, Anna Bednarek, Grzegorz Hibner, Paulina Czajka-Francuz, Sylwia Cisoń-Jurek, Dobromiła Karawasiecka, Bożena Szymczak, Jerzy Wojnar, Jerzy Chudek and Tomasz Francuz
Metabolites 2023, 13(9), 996; https://doi.org/10.3390/metabo13090996 - 06 Sep 2023
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Abstract
Background: The predictive role of vitamin D (VD) in breast cancer (BC) patients’ survival is still being investigated. This paper aims to evaluate the changes in VD metabolites during chemotherapy (CTH) and the predictive role of VD status in Caucasian BC patients treated [...] Read more.
Background: The predictive role of vitamin D (VD) in breast cancer (BC) patients’ survival is still being investigated. This paper aims to evaluate the changes in VD metabolites during chemotherapy (CTH) and the predictive role of VD status in Caucasian BC patients treated with CTH. Methods: Vitamin D and its metabolites were assessed with reference LC–MS/MS methodology in 98 consecutive BC patients starting CHT, after 3 and 6 months, and compared to the control group. Results: The frequency of VD deficiency in BC patients was greater than in the control group (56.1% vs. 37.2%). After 6 months of CTH, the number of VD-deficient BC patients slightly increased to 60%. The concentrations of VD active forms [25(OH)D2, 25(OH)D3], and catabolites [24,25(OH)2D3 and 3-epi-25(OH)D3] decreased after 3 and 6 months of CTH compared to the baseline values. Strong positive correlations between concentrations of 3-epi-25(OH)D3 and 25(OH)D in both groups were found. Similar correlations were also observed between 24,25(OH)2D3 and 25(OH)D levels. Kaplan–Meier survival analysis showed significantly longer survival in BC patients without deficiency (>20 ng/mL) at baseline (HR = 2.44 (95% CI 1.07–5.59), p = 0.026). Conclusions: (1) Our data provide further evidence that BC patients before CTH are more VD-deficient than the general population and this deficiency increases further during CTH treatment, as observed using the reference LC-MS methodology. (2) Presented results show that VD catabolism is not affected in BC patients. (3) The poorer survival in VD-deficient BP patients supports the importance of VD supplementation in BC patients with 25(OH)D levels below 20 ng/mL. Full article
(This article belongs to the Special Issue Metabolism and Cancer Biology)
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14 pages, 1836 KiB  
Article
Peripheral Blood Serum NMR Metabolomics Is a Powerful Tool to Discriminate Benign and Malignant Ovarian Tumors
by Sofia C. Nunes, Joana Sousa, Fernanda Silva, Margarida Silveira, António Guimarães, Jacinta Serpa, Ana Félix and Luís G. Gonçalves
Metabolites 2023, 13(9), 989; https://doi.org/10.3390/metabo13090989 - 01 Sep 2023
Viewed by 849
Abstract
Ovarian cancer is the major cause of death from gynecological cancer and the third most common gynecological malignancy worldwide. Despite a slight improvement in the overall survival of ovarian carcinoma patients in recent decades, the cure rate has not improved. This is mainly [...] Read more.
Ovarian cancer is the major cause of death from gynecological cancer and the third most common gynecological malignancy worldwide. Despite a slight improvement in the overall survival of ovarian carcinoma patients in recent decades, the cure rate has not improved. This is mainly due to late diagnosis and resistance to therapy. It is therefore urgent to develop effective methods for early detection and prognosis. We hypothesized that, besides being able to distinguish serum samples of patients with ovarian cancer from those of patients with benign ovarian tumors, 1H-NMR metabolomics analysis might be able to predict the malignant potential of tumors. For this, serum 1H-NMR metabolomics analyses were performed, including patients with malignant, benign and borderline ovarian tumors. The serum metabolic profiles were analyzed by multivariate statistical analysis, including principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) methods. A metabolic profile associated with ovarian malignant tumors was defined, in which lactate, 3-hydroxybutyrate and acetone were increased and acetate, histidine, valine and methanol were decreased. Our data support the use of 1H-NMR metabolomics analysis as a screening method for ovarian cancer detection and might be useful for predicting the malignant potential of borderline tumors. Full article
(This article belongs to the Special Issue Metabolism and Cancer Biology)
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