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Molecular Advances in Cancer and Cell Metabolism

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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: 20 January 2025 | Viewed by 12135

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Dr. Maria Concetta Faniello

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Research Center of Biochemistry and Advanced Molecular Biology, Department of Experimental and Clinical Medicine, “Magna Graecia” University of Catanzaro, 88100 Catanzaro, Italy
Interests: cell metabolism; antioxidants; transcription factors; gene expression; cancer metabolism

Dr. Maria Mesuraca

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Guest Editor

Department of Experimental and Clinical Medicine, University Magna Græcia, 88100 Catanzaro, Italy
Interests: cell metabolism; gene transfer; cell differentiation; signaling pathways; transcription factors
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Dear Colleagues,

Over the years, studies of cellular functions have allowed us to highlight how metabolism can be reprogrammed to support its links to many biological processes ranging from macromolecular synthesis to ATP production; in addition, cells continuously respond to different stimuli, growth factors, hormones, and changes in nutrient uptake by adapting metabolism to new conditions. Accumulating evidence suggests that metabolism can also regulate gene expression and signaling pathways, and its changes have significant impacts on many human diseases as well as recognized conditions associated with cancer.

The cellular metabolic phenotype is determined by the availability of metabolic substrates, oxygen levels, and interactions with the microenvironment where cells can proliferate and differentiate. The reprogramming of energy metabolism is a recognized hallmark of cancer cells that allows adaptation to new conditions of cell growth/survival through the metabolic switch from oxidative phosphorylation to glycolysis, when the aberrant proliferative capacity of cancer cells increases the energetic demands contributing to the neoplastic transformation.

The aim of this Special Issue is to collect the current advances of the metabolic regulation in human normal and tumor cells to better characterize the biochemical mechanism differences associated with tumor metabolic reprogramming. Original articles, short communications, and reviews from physiological and pathological molecular pathways such as those regarding integrative omics techniques are welcome.

We look forward to receiving your contributions.

Dr. Maria Concetta Faniello
Dr. Maria Mesuraca
Guest Editors

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Keywords

cell metabolism
cancer metabolism
cancer cell
oxidative stress
gene expression
signaling pathways
metabolic regulation
tumor growth
energy metabolism
metabolic phenotype
metabolic substrates

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Published Papers (9 papers)

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Research

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11 pages, 691 KiB

Open AccessArticle

The Association of TP53, BCL2, BAX and NOXA SNPs and Laryngeal Squamous Cell Carcinoma Development

by Tomas Jakstas, Agne Bartnykaite, Evaldas Padervinskis, Aurelija Vegiene, Elona Juozaityte, Virgilijus Uloza and Rasa Ugenskiene

Int. J. Mol. Sci. 2024, 25(21), 11849; https://doi.org/10.3390/ijms252111849 - 4 Nov 2024

Viewed by 628

Abstract

Head and neck cancer is the seventh leading cancer diagnosis worldwide. One of the most common cancers in the head and neck region is laryngeal cancer. In past years, the incidence of laryngeal squamous cell carcinoma has risen by 23%, and despite progress in treatment modalities, the survival rate has not changed. It is well known that genetic alterations may contribute to individuals’ susceptibility to cancer. Research of genetic alterations, such as single nucleotide polymorphisms, is essential to understanding carcinogenesis and susceptibility of laryngeal squamous cell carcinoma. A total of 200 LSCC patients and 200 controls were included in this retrospective case-control study; both groups were matched by age and sex. In the present study, we analyzed six SNPs in genes essential for apoptosis regulation: TP53 (rs9895829, rs17884306), BCL2 (rs1564483, rs4987855), BAX (rs704243), NOXA (PMAIP1) (rs1041978, rs78800940). We evaluated their associations with the risk of LSCC development, its pathomorphological manifestation, and patients’ overall survival rate. Genotyping was carried out using RT-PCR. The AG genotype of rs9895829 was more prevalent in controls than in cancer patients, leading to lower susceptibility to LSCC (OR = 0.301; 95%CI 0.096–0.940; p = 0.039). None of the analyzed SNPs showed an association with pathomorphological features of LSCC, but NOXA rs1041978 T allele carriers were found to be diagnosed with LSCC at an older age (OR = 1.962; 95%CI 1.072–3.592; p = 0.031). There was no statistically significant association between investigated SNPs and patient OS. The present study indicates that the AG genotype of rs9895829 provides a protective effect against LSCC development. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer and Cell Metabolism)

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25 pages, 18080 KiB

Open AccessArticle

Comprehensive Analysis and Verification of the Prognostic Significance of Cuproptosis-Related Genes in Colon Adenocarcinoma

by Yixiao Gu, Chengze Li, Yinan Yan, Jingmei Ming, Yuanhua Li, Xiang Chao and Tieshan Wang

Int. J. Mol. Sci. 2024, 25(21), 11830; https://doi.org/10.3390/ijms252111830 - 4 Nov 2024

Viewed by 741

Abstract

Colon adenocarcinoma (COAD) is a frequently occurring and lethal cancer. Cuproptosis is an emerging type of cell death, and the underlying pathways involved in this process in COAD remain poorly understood. Transcriptomic and clinical data for COAD patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. We investigated alterations in DNA and chromatin of cuproptosis-related genes (CRGs) in COAD. In order to identify predictive differentially expressed genes (DEGs) and various molecular subtypes, we used consensus cluster analysis. Through univariate, multivariate, and Lasso Cox regression analyses, four CRGs were identified. A risk prognostic model for cuproptosis characteristics was constructed based on four CRGs. This study also examined the association between the risk score and the tumor microenvironment (TME), the immune landscape, and drug sensitivity. We distinguished two unique molecular subtypes using consensus clustering analysis. We discovered that the clinical characteristics, prognosis, and TME cell infiltration characteristics of patients with multilayer CRG subtypes were all connected. The internal and external evaluations of the predicted accuracy of the prognostic model built using data derived from a cuproptosis risk score were completed at the same time. A nomogram and a clinical pathological analysis make it more useful in the field of medicine. A significant rise in immunosuppressive cells was observed in the high cuproptosis risk score group, with a correlation identified between the cuproptosis risk score and immune cell infiltration. Despite generally poor prognoses, the patients with a high cuproptosis risk but low tumor mutation burden (TMB), cancer stem cell (CSC) index, or microsatellite instability (MSI) may still benefit from immunotherapy. Furthermore, the cuproptosis risk score positively correlated with immune checkpoint gene expression. Analyzing the potential sensitivity to medications could aid in the development of clinical chemotherapy regimens and decision-making. CRGs are the subject of our in-depth study, which exposed an array of regulatory mechanisms impacting TME. In addition, we performed additional data mining into clinical features, prognosis effectiveness, and possible treatment medications. COAD’s molecular pathways will be better understood, leading to more precise treatment options. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer and Cell Metabolism)

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21 pages, 7361 KiB

Open AccessArticle

Vitamin B6 Pathway Maintains Glioblastoma Cell Survival in 3D Spheroid Cultures

by Najla Yussuf Moosa, Sara Abdullah Azeem, John K. Lodge, William Cheung and Shafiq Uddin Ahmed

Int. J. Mol. Sci. 2024, 25(19), 10428; https://doi.org/10.3390/ijms251910428 - 27 Sep 2024

Viewed by 805

Abstract

Glioblastoma (GBM) is a deadly brain cancer. The prognosis of GBM patients has marginally improved over the last three decades. The response of GBMs to initial treatment is inevitably followed by relapse. Thus, there is an urgent need to identify and develop new therapeutics to target this cancer and improve both patient outcomes and long-term survival. Metabolic reprogramming is considered one of the hallmarks of cancers. However, cell-based studies fail to accurately recapitulate the in vivo tumour microenvironment that influences metabolic signalling and rewiring. Against this backdrop, we conducted global, untargeted metabolomics analysis of the G7 and R24 GBM 2D monolayers and 3D spheroid cultures under identical cell culture conditions. Our studies revealed that the levels of multiple metabolites associated with the vitamin B6 pathway were significantly altered in 3D spheroids compared to the 2D monolayer cultures. Importantly, we show that pharmacological intervention with hydralazine, a small molecule that reduces vitamin B6 levels, resulted in the cell death of 3D GBM spheroid cultures. Thus, our study shows that inhibition of the vitamin B6 pathway is a novel therapeutic strategy for the development of targeted therapies in GBMs. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer and Cell Metabolism)

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19 pages, 2957 KiB

Open AccessArticle

Prostate Cancer’s Silent Partners: Fibroblasts and Their Influence on Glutamine Metabolism Manipulation

by Pia V. Hönscheid, Gustavo B. Baretton, Martin Puhr, Tiziana Siciliano, Justus S. Israel, Matthias B. Stope, Celina Ebersbach, Alicia-Marie K. Beier, Christian Thomas and Holger H. H. Erb

Int. J. Mol. Sci. 2024, 25(17), 9275; https://doi.org/10.3390/ijms25179275 - 27 Aug 2024

Viewed by 932

Abstract

Cancer-associated fibroblast (CAF)s in the tumour microenvironment (TME) modulate the extracellular matrix, interact with cancer cells, and facilitate communication with infiltrating leukocytes, significantly contributing to cancer progression and therapeutic response. In prostate cancer (PCa), CAFs promote malignancy through metabolic rewiring, cancer stem cell regulation, and therapy resistance. Pre-clinical studies indicate that targeting amino acid metabolism, particularly glutamine (Gln) metabolism, reduces cancer proliferation and stemness. However, most studies lack the context of CAF–cancer interaction, focusing on monocultures. This study assesses the influence of CAFs on PCa growth by manipulating Gln metabolism using colour-labelled PCa cell lines (red) and fibroblast (green) in a co-culture system to evaluate CAFs’ effects on PCa cell proliferation and clonogenic potential. CAFs increased the proliferation of hormone-sensitive LNCaP cells, whereas the castration-resistant C4-2 cells were unaffected. However, clonogenic growth increased in both cell lines. Gln deprivation and GLS1 inhibition experiments revealed that the increased growth rate of LNCAP cells was associated with increased dependence on Gln, which was confirmed by proteomic analyses. Tissue analysis of PCa patients revealed elevated GLS1 levels in both the PCa epithelium and stroma, suggesting that GLS1 is a therapeutic target. Moreover, the median overall survival analysis of GLS1 expression in the PCa epithelium and stroma identified a “high-risk” patient group that may benefit from GLS1-targeted therapies. Therefore, GLS1 targeting appears promising in castration-resistant PCa patients with high GLS1 epithelium and low GLS1 stromal expression. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer and Cell Metabolism)

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15 pages, 2331 KiB

Open AccessArticle

Synergy between PEDF and Doxorubicin in Breast Cancer Cells: Effects on Metastatic and Metabolic Pathways

by Raziyeh Abooshahab, Hani Al-Salami and Crispin R. Dass

Int. J. Mol. Sci. 2024, 25(5), 2755; https://doi.org/10.3390/ijms25052755 - 27 Feb 2024

Cited by 1 | Viewed by 1484

Abstract

Pigment epithelium-derived factor (PEDF), a serine protease inhibitor (Serpin) family member, shows promise in inhibiting tumour growth. In our study, we explored the effects of PEDF on the efficacy of the frontline chemotherapy agent doxorubicin (Dox) in BC cells. We found that Dox+PEDF treatment significantly reduced glucose uptake in MDA-MB-231 cells compared to the control (p = 0.0005), PEDF (p = 0.0137), and Dox (p = 0.0171) alone but paradoxically increased it in MCF-7 cells. Our findings further revealed that PEDF, Dox, and Dox+PEDF substantially hindered tumour cell migration from tumour spheroids, with Dox+PEDF showing the most significant impact (p < 0.0001). We also observed notable decreases in the expression of metastatic markers (uPAR, uPA, CXCR4, MT1-MMP, TNF-α) across all treatment groups (p < 0.0001) in both cell lines. When it comes to metabolic pathways, PEDF increased phosphorylated IRS-1 (p-IRS1) levels in MDA-MB-231 and MCF-7 (p < 0.0001), while Dox decreased it, and the combination led to an increase. In MDA-MB-231 cells, treatment with PEDF, Dox, and the combination led to a notable decrease in both phosphorylated AKT (p-AKT) and total AKT levels. In MCF-7, while PEDF, Dox, and their combination led to a reduction in p-AKT, total levels of AKT increased in the presence of Dox and Dox+PEDF. Combining PEDF with Dox enhances the targeting of metastatic and metabolic pathways in breast cancer cell lines. This synergy, marked by PEDF’s increasing roles in cancer control, may pave the way for more effective cancer treatments. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer and Cell Metabolism)

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Review

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23 pages, 1821 KiB

Open AccessReview

FOSL1’s Oncogene Roles in Glioma/Glioma Stem Cells and Tumorigenesis: A Comprehensive Review

by Azam Khedri, Shanchun Guo, Vanajothi Ramar, BreAnna Hudson and Mingli Liu

Int. J. Mol. Sci. 2024, 25(10), 5362; https://doi.org/10.3390/ijms25105362 - 14 May 2024

Viewed by 1917

Abstract

This review specifically examines the important function of the oncoprotein FOSL1 in the dimeric AP-1 transcription factor, which consists of FOS-related components. FOSL1 is identified as a crucial controller of invasion and metastatic dissemination, making it a potential target for therapeutic treatment in cancer patients. The review offers a thorough examination of the regulatory systems that govern the influence exerted on FOSL1. These include a range of changes that occur throughout the process of transcription and after the translation of proteins. We have discovered that several non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), play a significant role in regulating FOSL1 expression by directly interacting with its mRNA transcripts. Moreover, an investigation into the functional aspects of FOSL1 reveals its involvement in apoptosis, proliferation, and migration. This work involves a comprehensive analysis of the complex signaling pathways that support these diverse activities. Furthermore, particular importance is given to the function of FOSL1 in coordinating the activation of several cytokines, such as TGF-beta, and the commencement of IL-6 and VEGF production in tumor-associated macrophages (TAMs) that migrate into the tumor microenvironment. There is a specific emphasis on evaluating the predictive consequences linked to FOSL1. Insights are now emerging on the developing roles of FOSL1 in relation to the processes that drive resistance and reliance on specific treatment methods. Targeting FOSL1 has a strong inhibitory effect on the formation and spread of specific types of cancers. Despite extensive endeavors, no drugs targeting AP-1 or FOSL1 for cancer treatment have been approved for clinical use. Hence, it is imperative to implement innovative approaches and conduct additional verifications. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer and Cell Metabolism)

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22 pages, 1078 KiB

Open AccessReview

Possible Strategies to Reduce the Tumorigenic Risk of Reprogrammed Normal and Cancer Cells

by Ying-Chu Lin, Cha-Chien Ku, Kenly Wuputra, Chung-Jung Liu, Deng-Chyang Wu, Maki Satou, Yukio Mitsui, Shigeo Saito and Kazunari K. Yokoyama

Int. J. Mol. Sci. 2024, 25(10), 5177; https://doi.org/10.3390/ijms25105177 - 9 May 2024

Cited by 1 | Viewed by 1619

Abstract

The reprogramming of somatic cells to pluripotent stem cells has immense potential for use in regenerating or redeveloping tissues for transplantation, and the future application of this method is one of the most important research topics in regenerative medicine. These cells are generated from normal cells, adult stem cells, or neoplastic cancer cells. They express embryonic stem cell markers, such as OCT4, SOX2, and NANOG, and can differentiate into all tissue types in adults, both in vitro and in vivo. However, tumorigenicity, immunogenicity, and heterogeneity of cell populations may hamper the use of this method in medical therapeutics. The risk of cancer formation is dependent on mutations of these stemness genes during the transformation of pluripotent stem cells to cancer cells and on the alteration of the microenvironments of stem cell niches at genetic and epigenetic levels. Recent reports have shown that the generation of induced pluripotent stem cells (iPSCs) derived from human fibroblasts could be induced using chemicals, which is a safe, easy, and clinical-grade manufacturing strategy for modifying the cell fate of human cells required for regeneration therapies. This strategy is one of the future routes for the clinical application of reprogramming therapy. Therefore, this review highlights the recent progress in research focused on decreasing the tumorigenic risk of iPSCs or iPSC-derived organoids and increasing the safety of iPSC cell preparation and their application for therapeutic benefits. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer and Cell Metabolism)

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20 pages, 1923 KiB

Open AccessReview

Exploring the Enigma: The Role of the Epithelial Protein Lost in Neoplasm in Normal Physiology and Cancer Pathogenesis

by Emma Lindell and Xiaonan Zhang

Int. J. Mol. Sci. 2024, 25(9), 4970; https://doi.org/10.3390/ijms25094970 - 2 May 2024

Viewed by 1066

Abstract

The cytoskeleton plays a pivotal role in maintaining the epithelial phenotype and is vital to several hallmark processes of cancer. Over the past decades, researchers have identified the epithelial protein lost in neoplasm (EPLIN, also known as LIMA1) as a key regulator of cytoskeletal dynamics, cytoskeletal organization, motility, as well as cell growth and metabolism. Dysregulation of EPLIN is implicated in various aspects of cancer progression, such as tumor growth, invasion, metastasis, and therapeutic resistance. Its altered expression levels or activity can disrupt cytoskeletal dynamics, leading to aberrant cell motility and invasiveness characteristic of malignant cells. Moreover, the involvement of EPLIN in cell growth and metabolism underscores its significance in orchestrating key processes essential for cancer cell survival and proliferation. This review provides a comprehensive exploration of the intricate roles of EPLIN across diverse cellular processes in both normal physiology and cancer pathogenesis. Additionally, this review discusses the possibility of EPLIN as a potential target for anticancer therapy in future studies. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer and Cell Metabolism)

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18 pages, 1941 KiB

Open AccessReview

A Systematic Review of the Metabolism of High-Grade Gliomas: Current Targeted Therapies and Future Perspectives

by Lucio De Maria, Pier Paolo Panciani, Marco Zeppieri, Tamara Ius, Simona Serioli, Amedeo Piazza, Emanuele Di Giovanni, Marco Maria Fontanella and Edoardo Agosti

Int. J. Mol. Sci. 2024, 25(2), 724; https://doi.org/10.3390/ijms25020724 - 5 Jan 2024

Cited by 2 | Viewed by 1710

Abstract

High-grade glial tumors (HGGs) exhibit aggressive growth patterns and high recurrence rates. The prevailing treatment approach comprises radiation therapy (RT), chemotherapy (CMT), and surgical resection. Despite the progress made in traditional treatments, the outlook for patients with HGGs remains bleak. Tumor metabolism is emerging as a potential target for glioma therapies, a promising approach that harnesses the metabolism to target tumor cells. However, the efficacy of therapies targeting the metabolism of HGGs remains unclear, compelling a comprehensive review. This study aimed to assess the outcome of present trials on HGG therapies targeting metabolism. A comprehensive search of PubMed, Ovid MEDLINE, and Ovid EMBASE was conducted until November 2023. The search method used pertinent Medical Subject Heading (MeSH) terminologies and keywords referring to “high-grade gliomas”, “metabolism”, “target therapies”, “monoclonal antibodies”, “overall survival”, and “progression-free survival”. The review analyzed studies that focused on therapies targeting the metabolism of HGGs in human subjects. These studies included both randomized controlled trials (RCTs) and non-randomized controlled trials (NRCTs). Out of 284 articles identified, 23 trials met the inclusion criteria and were thoroughly analyzed. Phase II trials were the most numerous (62%). Targeted metabolic therapies were predominantly used for recurrent HGGs (67%). The most common targeted pathways were the vascular endothelial growth factor (VEGF, 43%), the human epidermal growth factor receptor (HER, 22%), the platelet-derived growth factor (PDGF, 17%), and the mammalian target of rapamycin (mTOR, 17%). In 39% of studies, the subject treatment was combined with CMT (22%), RT (4%), or both (13%). The median OS widely ranged from 4 to 26.3 months, while the median PFS ranged from 1.5 to 13 months. This systematic literature review offers a thorough exploration of the present state of metabolic therapies for HGGs. The multitude of targeted pathways underscores the intricate nature of addressing the metabolic aspects of these tumors. Despite existing challenges, these findings provide valuable insights, guiding future research endeavors. The results serve as a foundation for refining treatment strategies and enhancing patient outcomes within the complex landscape of HGGs. Full article

(This article belongs to the Special Issue Molecular Advances in Cancer and Cell Metabolism)

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