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6 pages, 232 KiB

Open AccessEditorial

Cancer Metabolism as a New Real Target in Tumor Therapy

by Ferdinando Chiaradonna and Domenica Scumaci

Cells 2021, 10(6), 1393; https://doi.org/10.3390/cells10061393 - 5 Jun 2021

Cited by 4 | Viewed by 2834

Abstract

Cancer cells exhibit common hallmarks consisting of specific competencies acquired during the tumorigenesis process, including stimulation of cancer cell proliferation, insensitivity to growth signal inhibition, apoptosis evasion, enhancement of replicative potential, induction of angiogenesis, and tissue invasion and metastasis [...] Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

Research

Jump to: Editorial, Review

19 pages, 2980 KiB

Open AccessArticle

Suppression of the HBP Function Increases Pancreatic Cancer Cell Sensitivity to a Pan-RAS Inhibitor

by Francesca Ricciardiello, Laura Bergamaschi, Humberto De Vitto, Yang Gang, Taiping Zhang, Roberta Palorini and Ferdinando Chiaradonna

Cells 2021, 10(2), 431; https://doi.org/10.3390/cells10020431 - 18 Feb 2021

Cited by 17 | Viewed by 4619

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death and the search for a resolutive therapy is still a challenge. Since KRAS is commonly mutated in PDAC and is one of the main drivers of PDAC progression, its inhibition should be [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death and the search for a resolutive therapy is still a challenge. Since KRAS is commonly mutated in PDAC and is one of the main drivers of PDAC progression, its inhibition should be a key strategy for treatment, especially considering the recent development of specific KRAS inhibitors. Nevertheless, the effects of KRAS inhibition can be increased through the co-inhibition of other nodes important for cancer development. One of them could be the hexosamine biosynthetic pathway (HBP), whose enhancement is considered fundamental for PDAC. Here, we demonstrate that PDAC cells expressing oncogenic KRAS, owing to an increase in the HBP flux, become strongly reliant on HBP for both proliferation and survival. In particular, upon treatment with two different compounds, 2-deoxyglucose and FR054, inhibiting both HBP and protein N-glycosylation, these cells undergo apoptosis significantly more than PDAC cells expressing wild-type KRAS. Importantly, we also show that the combined treatment between FR054 and the pan-RAS inhibitor BI-2852 has an additive negative effect on cell proliferation and survival by means of the suppression of both Akt activity and cyclin D1 expression. Thus, co-inhibition of HBP and oncogenic RAS may represent a novel therapy for PDAC patients. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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15 pages, 3502 KiB

Open AccessArticle

Genetic Perturbation of Pyruvate Dehydrogenase Kinase 1 Modulates Growth, Angiogenesis and Metabolic Pathways in Ovarian Cancer Xenografts

by Carolina Venturoli, Ilaria Piga, Matteo Curtarello, Martina Verza, Giovanni Esposito, Santina Venuto, Filippo Navaglia, Angela Grassi and Stefano Indraccolo

Cells 2021, 10(2), 325; https://doi.org/10.3390/cells10020325 - 5 Feb 2021

Cited by 11 | Viewed by 2887

Abstract

Pyruvate dehydrogenase kinase 1 (PDK1) blockade triggers are well characterized in vitro metabolic alterations in cancer cells, including reduced glycolysis and increased glucose oxidation. Here, by gene expression profiling and digital pathology-mediated quantification of in situ markers in tumors, we investigated effects of [...] Read more.

Pyruvate dehydrogenase kinase 1 (PDK1) blockade triggers are well characterized in vitro metabolic alterations in cancer cells, including reduced glycolysis and increased glucose oxidation. Here, by gene expression profiling and digital pathology-mediated quantification of in situ markers in tumors, we investigated effects of PDK1 silencing on growth, angiogenesis and metabolic features of tumor xenografts formed by highly glycolytic OC316 and OVCAR3 ovarian cancer cells. Notably, at variance with the moderate antiproliferative effects observed in vitro, we found a dramatic negative impact of PDK1 silencing on tumor growth. These findings were associated with reduced angiogenesis and increased necrosis in the OC316 and OVCAR3 tumor models, respectively. Analysis of viable tumor areas uncovered increased proliferation as well as increased apoptosis in PDK1-silenced OVCAR3 tumors. Moreover, RNA profiling disclosed increased glucose catabolic pathways—comprising both oxidative phosphorylation and glycolysis—in PDK1-silenced OVCAR3 tumors, in line with the high mitotic activity detected in the viable rim of these tumors. Altogether, our findings add new evidence in support of a link between tumor metabolism and angiogenesis and remark on the importance of investigating net effects of modulations of metabolic pathways in the context of the tumor microenvironment. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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16 pages, 8355 KiB

Open AccessArticle

Contribution of the CK2 Catalytic Isoforms α and α’ to the Glycolytic Phenotype of Tumor Cells

by Francesca Zonta, Christian Borgo, Camila Paz Quezada Meza, Ionica Masgras, Andrea Rasola, Mauro Salvi, Lorenzo A. Pinna and Maria Ruzzene

Cells 2021, 10(1), 181; https://doi.org/10.3390/cells10010181 - 18 Jan 2021

Cited by 8 | Viewed by 3252

Abstract

CK2 is a Ser/Thr protein kinase overexpressed in many cancers. It is usually present in cells as a tetrameric enzyme, composed of two catalytic (α or α’) and two regulatory (β) subunits, but it is active also in its monomeric form, and the [...] Read more.

CK2 is a Ser/Thr protein kinase overexpressed in many cancers. It is usually present in cells as a tetrameric enzyme, composed of two catalytic (α or α’) and two regulatory (β) subunits, but it is active also in its monomeric form, and the specific role of the different isoforms is largely unknown. CK2 phosphorylates several substrates related to the uncontrolled proliferation, motility, and survival of cancer cells. As a consequence, tumor cells are addicted to CK2, relying on its activity more than healthy cells for their life, and exploiting it for developing multiple oncological hallmarks. However, little is known about CK2 contribution to the metabolic rewiring of cancer cells. With this study we aimed at shedding some light on it, especially focusing on the CK2 role in the glycolytic onco-phenotype. By analyzing neuroblastoma and osteosarcoma cell lines depleted of either one (α) or the other (α’) CK2 catalytic subunit, we also aimed at disclosing possible pro-tumor functions which are specific of a CK2 isoform. Our results suggest that both CK2 α and α’ contribute to cell proliferation, survival and tumorigenicity. The analyzed metabolic features disclosed a role of CK2 in tumor metabolism, and suggest prominent functions for CK2 α isoform. Results were also confirmed by CK2 pharmacological inhibition. Overall, our study provides new information on the mechanism of cancer cells addiction to CK2 and on its isoform-specific functions, with fundamental implications for improving future therapeutic strategies based on CK2 targeting. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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15 pages, 3404 KiB

Open AccessArticle

Exogenous Fatty Acids Modulate ER Lipid Composition and Metabolism in Breast Cancer Cells

by Angela Maria Rizzo, Irma Colombo, Gigliola Montorfano, Stefania Zava and Paola Antonia Corsetto

Cells 2021, 10(1), 175; https://doi.org/10.3390/cells10010175 - 16 Jan 2021

Cited by 18 | Viewed by 4160

Abstract

(1) Background: Lipid metabolism is a fundamental hallmark of all tumors, especially of breast cancer. Few studies describe the different lipid metabolisms and sensitivities to the microenvironment of breast cancer cell subtypes that influence the proliferation, aggressiveness, and success of therapy. This study [...] Read more.

(1) Background: Lipid metabolism is a fundamental hallmark of all tumors, especially of breast cancer. Few studies describe the different lipid metabolisms and sensitivities to the microenvironment of breast cancer cell subtypes that influence the proliferation, aggressiveness, and success of therapy. This study describes the impact of lipid microenvironment on endoplasmic reticulum (ER) membrane and metabolic activity in two breast cancer cell lines with Luminal A and triple-negative breast cancer (TNBC) features. (2) Methods: We investigated the peculiar lipid phenotype of a TNBC cell line, MDA-MB-231, and a Luminal A cell line, MCF7, and their different sensitivity to exogenous fatty acids (i.e., palmitic acid (PA) and docosahexaenoic acid (DHA)). Moreover, we verified the impact of exogenous fatty acids on ER lipid composition. (3) Results: The data obtained demonstrate that MDA-MB-231 cells are more sensitive to the lipid microenvironment and that both PA and DHA are able to remodel their ER membranes with consequences on resident enzyme activity. On the contrary, MCF7 cells are less sensitive to PA, whereas they incorporate DHA, although less efficiently than MDA-MB-231 cells. (4) Conclusions: This study sustains the importance of lipid metabolism as an innovative hallmark to discriminate breast cancer subclasses and to develop personalized and innovative pharmacological strategies. The different sensitivities to the lipid environment shown by MCF7 and MDA-MB-231 cells might be related to cell malignancy and chemoresistance onset. In the future, this new approach could lead to a substantial decrease both in deleterious side effects for the patients and in the cost of entire therapeutic treatments coupled with increased therapy efficiency. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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26 pages, 7643 KiB

Open AccessArticle

Profiling and Targeting of Energy and Redox Metabolism in Grade 2 Bladder Cancer Cells with Different Invasiveness Properties

by Valentina Pasquale, Giacomo Ducci, Gloria Campioni, Adria Ventrici, Chiara Assalini, Stefano Busti, Marco Vanoni, Riccardo Vago and Elena Sacco

Cells 2020, 9(12), 2669; https://doi.org/10.3390/cells9122669 - 11 Dec 2020

Cited by 20 | Viewed by 5436

Abstract

Bladder cancer is one of the most prevalent deadly diseases worldwide. Grade 2 tumors represent a good window of therapeutic intervention, whose optimization requires high resolution biomarker identification. Here we characterize energy metabolism and cellular properties associated with spreading and tumor progression of [...] Read more.

Bladder cancer is one of the most prevalent deadly diseases worldwide. Grade 2 tumors represent a good window of therapeutic intervention, whose optimization requires high resolution biomarker identification. Here we characterize energy metabolism and cellular properties associated with spreading and tumor progression of RT112 and 5637, two Grade 2 cancer cell lines derived from human bladder, representative of luminal-like and basal-like tumors, respectively. The two cell lines have similar proliferation rates, but only 5637 cells show efficient lateral migration. In contrast, RT112 cells are more prone to form spheroids. RT112 cells produce more ATP by glycolysis and OXPHOS, present overall higher metabolic plasticity and are less sensitive than 5637 to nutritional perturbation of cell proliferation and migration induced by treatment with 2-deoxyglucose and metformin. On the contrary, spheroid formation is less sensitive to metabolic perturbations in 5637 than RT112 cells. The ability of metformin to reduce, although with different efficiency, cell proliferation, sphere formation and migration in both cell lines, suggests that OXPHOS targeting could be an effective strategy to reduce the invasiveness of Grade 2 bladder cancer cells. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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17 pages, 3668 KiB

Open AccessArticle

Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer

by Shiv Verma, Eswar Shankar, E. Ricky Chan and Sanjay Gupta

Cells 2020, 9(12), 2535; https://doi.org/10.3390/cells9122535 - 24 Nov 2020

Cited by 22 | Viewed by 4424

Abstract

Androgen deprivation therapy (ADT) is standard-of-care for advanced-stage prostate cancer, and enzalutamide (Xtandi^®, Astellas, Northbrook, IL, USA), a second generation antiandrogen, is prescribed in this clinical setting. The response to this medication is usually temporary with the rapid emergence of drug [...] Read more.

Androgen deprivation therapy (ADT) is standard-of-care for advanced-stage prostate cancer, and enzalutamide (Xtandi^®, Astellas, Northbrook, IL, USA), a second generation antiandrogen, is prescribed in this clinical setting. The response to this medication is usually temporary with the rapid emergence of drug resistance. A better understanding of gene expression changes associated with enzalutamide resistance will facilitate circumventing this problem. We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-2B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation. Next-Gen sequencing detected 9409 and 7757 genes differentially expressed in LNCaP and C4-2B cells, compared to their parental counterparts. A subset of differentially expressed genes were validated by qRT-PCR. Analysis by the i-pathway revealed membrane transporters including solute carrier proteins, ATP-binding cassette transporters, and drug metabolizing enzymes as the most prominent genes dysregulated in resistant cell lines. RNA-Seq data demonstrated predominance of solute carrier genes SLC12A5, SLC25A17, and SLC27A6 during metabolic reprogramming and development of drug resistance. Upregulation of these genes were associated with higher uptake of lactic/citric acid and lower glucose intake in resistant cells. Our data suggest the predominance of solute carrier genes during metabolic reprogramming of prostate cancer cells in an androgen-deprived environment, thus signifying them as potentially attractive therapeutic targets. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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25 pages, 3029 KiB

Open AccessArticle

Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells

by Jacopo Albanesi, Nelida Ines Noguera, Cristina Banella, Tommaso Colangelo, Elisabetta De Marinis, Stefano Leone, Orazio Palumbo, Maria Teresa Voso, Paolo Ascenzi, Clara Nervi, Fabrizio Bianchi and Alessandra di Masi

Cells 2020, 9(11), 2423; https://doi.org/10.3390/cells9112423 - 5 Nov 2020

Cited by 15 | Viewed by 4747

Abstract

Acute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all-trans retinoic acid (ATRA) [...] Read more.

Acute promyelocytic leukemia (APL) is a hematological disease characterized by a balanced reciprocal translocation that leads to the synthesis of the oncogenic fusion protein PML-RARα. APL is mainly managed by a differentiation therapy based on the administration of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). However, therapy resistance, differentiation syndrome, and relapses require the development of new low-toxicity therapies based on the induction of blasts differentiation. In keeping with this, we reasoned that a better understanding of the molecular mechanisms pivotal for ATRA-driven differentiation could definitely bolster the identification of new therapeutic strategies in APL patients. We thus performed an in-depth high-throughput transcriptional profile analysis and metabolic characterization of a well-established APL experimental model based on NB4 cells that represent an unevaluable tool to dissect the complex mechanism associated with ATRA-induced granulocytic differentiation. Pathway-reconstruction analysis using genome-wide transcriptional data has allowed us to identify the activation/inhibition of several cancer signaling pathways (e.g., inflammation, immune cell response, DNA repair, and cell proliferation) and master regulators (e.g., transcription factors, epigenetic regulators, and ligand-dependent nuclear receptors). Furthermore, we provide evidence of the regulation of a considerable set of metabolic genes involved in cancer metabolic reprogramming. Consistently, we found that ATRA treatment of NB4 cells drives the activation of aerobic glycolysis pathway and the reduction of OXPHOS-dependent ATP production. Overall, this study represents an important resource in understanding the molecular “portfolio” pivotal for APL differentiation, which can be explored for developing new therapeutic strategies. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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21 pages, 3219 KiB

Open AccessArticle

Structural Basis of Inhibition of the Pioneer Transcription Factor NF-Y by Suramin

by Valentina Nardone, Antonio Chaves-Sanjuan, Michela Lapi, Cristina Airoldi, Andrea Saponaro, Sebastiano Pasqualato, Diletta Dolfini, Carlo Camilloni, Andrea Bernardini, Nerina Gnesutta, Roberto Mantovani and Marco Nardini

Cells 2020, 9(11), 2370; https://doi.org/10.3390/cells9112370 - 29 Oct 2020

Cited by 9 | Viewed by 4096

Abstract

NF-Y is a transcription factor (TF) comprising three subunits (NF-YA, NF-YB, NF-YC) that binds with high specificity to the CCAAT sequence, a widespread regulatory element in gene promoters of prosurvival, cell-cycle-promoting, and metabolic genes. Tumor cells undergo “metabolic rewiring” through overexpression of genes [...] Read more.

NF-Y is a transcription factor (TF) comprising three subunits (NF-YA, NF-YB, NF-YC) that binds with high specificity to the CCAAT sequence, a widespread regulatory element in gene promoters of prosurvival, cell-cycle-promoting, and metabolic genes. Tumor cells undergo “metabolic rewiring” through overexpression of genes involved in such pathways, many of which are under NF-Y control. In addition, NF-YA appears to be overexpressed in many tumor types. Thus, limiting NF-Y activity may represent a desirable anti-cancer strategy, which is an ongoing field of research. With virtual-screening docking simulations on a library of pharmacologically active compounds, we identified suramin as a potential NF-Y inhibitor. We focused on suramin given its high water-solubility that is an important factor for in vitro testing, since NF-Y is sensitive to DMSO. By electrophoretic mobility shift assays (EMSA), isothermal titration calorimetry (ITC), STD NMR, X-ray crystallography, and molecular dynamics (MD) simulations, we showed that suramin binds to the histone fold domains (HFDs) of NF-Y, preventing DNA-binding. Our analyses, provide atomic-level detail on the interaction between suramin and NF-Y and reveal a region of the protein, nearby the suramin-binding site and poorly conserved in other HFD-containing TFs, that may represent a promising starting point for rational design of more specific and potent inhibitors with potential therapeutic applications. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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24 pages, 4255 KiB

Open AccessFeature PaperArticle

DJ-1 Proteoforms in Breast Cancer Cells: The Escape of Metabolic Epigenetic Misregulation

by Domenica Scumaci, Erika Olivo, Claudia Vincenza Fiumara, Marina La Chimia, Maria Teresa De Angelis, Sabrina Mauro, Giosuè Costa, Francesca Alessandra Ambrosio, Stefano Alcaro, Valter Agosti, Francesco Saverio Costanzo and Giovanni Cuda

Cells 2020, 9(9), 1968; https://doi.org/10.3390/cells9091968 - 26 Aug 2020

Cited by 25 | Viewed by 4528

Abstract

Enhanced glycolysis is a hallmark of breast cancer. In cancer cells, the high glycolytic flux induces carbonyl stress, a damaging condition in which the increase of reactive carbonyl species makes DNA, proteins, and lipids more susceptible to glycation. Together with glucose, methylglyoxal (MGO), [...] Read more.

Enhanced glycolysis is a hallmark of breast cancer. In cancer cells, the high glycolytic flux induces carbonyl stress, a damaging condition in which the increase of reactive carbonyl species makes DNA, proteins, and lipids more susceptible to glycation. Together with glucose, methylglyoxal (MGO), a byproduct of glycolysis, is considered the main glycating agent. MGO is highly diffusible, enters the nucleus, and can react with easily accessible lysine- and arginine-rich tails of histones. Glycation adducts on histones undergo oxidization and further rearrange to form stable species known as advanced glycation end-products (AGEs). This modification alters nucleosomes stability and chromatin architecture deconstructing the histone code. Formation of AGEs has been associated with cancer, diabetes, and several age-related diseases. Recently, DJ-1, a cancer-associated protein that protects cells from oxidative stress, has been described as a deglycase enzyme. Although its role in cell survival results still controversial, in several human tumors, its expression, localization, oxidation, and phosphorylation were found altered. This work aimed to explore the molecular mechanism that triggers the peculiar cellular compartmentalization and the specific post-translational modifications (PTM) that, occurring in breast cancer cells, influences the DJ-1 dual role. Using a proteomic approach, we identified on DJ-1 a novel threonine phosphorylation (T125) that was found, by the in-silico tool scansite 4, as part of a putative Akt consensus. Notably, this threonine is in addition to histidine 126, a key residue involved in the formation of catalytic triade (glu18-Cys106-His126) inside the glioxalase active site of DJ. Interestingly, we found that pharmacological modulation of Akt pathway induces a functional tuning of DJ-1 proteoforms, as well as their shuttle from cytosol to nucleus, pointing out that pathway as critical in the development of DJ-1 pro-tumorigenic abilities. Deglycase activity of DJ-1 on histones proteins, investigated by coupling 2D tau gel with LC-MS/MS and 2D-TAU (Triton-Acid-Urea)-Western blot, was found correlated with its phosphorylation status that, in turn, depends from Akt activation. In normal conditions, DJ-1 acts as a redox-sensitive chaperone and as an oxidative stress sensor. In cancer cells, glycolytic rewiring, inducing increased reactive oxygen species (ROS) levels, enhances AGEs products. Alongside, the moderate increase of ROS enhances Akt signaling that induces DJ-1-phosphorylation. When phosphorylated DJ-1 increases its glyoxalase activity, the level of AGEs on histones decreases. Therefore, phospho-DJ-1 prevents glycation-induced histones misregulation and its Akt-related hyperactivity represents a way to preserve the epigenome landscape sustaining proliferation of cancer cells. Together, these results shed light on an interesting mechanism that cancer cells might execute to escape the metabolic induced epigenetic misregulation that otherwise could impair their malignant proliferative potential. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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24 pages, 9559 KiB

Open AccessArticle

Cholesterol and Mevalonate: Two Metabolites Involved in Breast Cancer Progression and Drug Resistance through the ERRα Pathway

by Matteo Brindisi, Marco Fiorillo, Luca Frattaruolo, Federica Sotgia, Michael P. Lisanti and Anna Rita Cappello

Cells 2020, 9(8), 1819; https://doi.org/10.3390/cells9081819 - 31 Jul 2020

Cited by 42 | Viewed by 5769

Abstract

Breast cancer is the second greatest cause of cancer-related death in women. Resistance to endocrine treatments or chemotherapy is a limiting drawback. In this context, this work aims to evaluate the effects of cholesterol and mevalonate during tumor progression and their contribution in [...] Read more.

Breast cancer is the second greatest cause of cancer-related death in women. Resistance to endocrine treatments or chemotherapy is a limiting drawback. In this context, this work aims to evaluate the effects of cholesterol and mevalonate during tumor progression and their contribution in the onset of resistance to clinical treatments in use today. In this study, we demonstrated that cholesterol and mevalonate treatments were able to activate the estrogen-related receptor alpha (ERRα) pathway, increasing the expression levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), ERbB2/human epithelial receptor (HER2), tumor protein D52 (TPD52), and NOTCH2 proteins in breast cancer cells. The activation of this pathway is shown to be responsible for intense metabolic switching, higher proliferation rates, sustained motility, the propagation of cancer stem-like cells (CSCs), and lipid droplet formation. All of these events are related to greater tumor propagation, aggressiveness, and drug resistance. Furthermore, the activation and expression of proteins induced by the treatment with cholesterol or mevalonate are consistent with those obtained from the MCF-7/TAMr cell line, which is largely used as a breast cancer model of acquired endocrine therapy resistance. Altogether, our data indicate that cholesterol and mevalonate are two metabolites implicated in breast cancer progression, aggressiveness, and drug resistance, through the activation of the ERRα pathway. Our findings enable us to identify the ERRα receptor as a poor prognostic marker in patients with breast carcinoma, suggesting the correlation between cholesterol/mevalonate and ERRα as a new possible target in breast cancer treatment. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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12 pages, 8199 KiB

Open AccessArticle

Glutaminase Inhibition on NSCLC Depends on Extracellular Alanine Exploitation

by Elisa Caiola, Marika Colombo, Giovanna Sestito, Monica Lupi, Mirko Marabese, Roberta Pastorelli, Massimo Broggini and Laura Brunelli

Cells 2020, 9(8), 1766; https://doi.org/10.3390/cells9081766 - 23 Jul 2020

Cited by 19 | Viewed by 4413

Abstract

Non-small-cell lung cancer (NSCLC) cell lines vary in their sensitivity to glutaminase inhibitors, so it is important to identify the metabolic assets underling their efficacy in cancer cells. Even though specific genetic lesions such as in KRAS and LKB1 have been associated with [...] Read more.

Non-small-cell lung cancer (NSCLC) cell lines vary in their sensitivity to glutaminase inhibitors, so it is important to identify the metabolic assets underling their efficacy in cancer cells. Even though specific genetic lesions such as in KRAS and LKB1 have been associated with reliance on glutamine for their metabolic needs, we found no distinction between glutaminase inhibitor CB-839 sensitivity and resistant phenotypes in NSCLC cells with or without these genetic alterations. We demonstrated the close relationship between environmental alanine uptake and catabolism. This response depended on the individual cell’s ability to employ alanine aminotransferase (GPT2) to compensate the reduced glutamate availability. It may, therefore, be useful to determine GPT2 levels to predict which NSCLC patients would benefit most from glutaminase inhibitor treatment. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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25 pages, 3948 KiB

Open AccessArticle

Progressively De-Differentiated Pancreatic Cancer Cells Shift from Glycolysis to Oxidative Metabolism and Gain a Quiescent Stem State

by Giulia Ambrosini, Elisa Dalla Pozza, Giuseppina Fanelli, Claudia Di Carlo, Andrea Vettori, Giuseppe Cannino, Chiara Cavallini, Cristian Andres Carmona-Carmona, Jessica Brandi, Sara Rinalducci, Maria Teresa Scupoli, Andrea Rasola, Daniela Cecconi, Marta Palmieri and Ilaria Dando

Cells 2020, 9(7), 1572; https://doi.org/10.3390/cells9071572 - 28 Jun 2020

Cited by 21 | Viewed by 4607

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is typically characterized by high chemoresistance and metastatic spread, features mainly attributable to cancer stem cells (CSCs). It is of central interest the characterization of CSCs and, in particular, the study of their metabolic features in order to selectively [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is typically characterized by high chemoresistance and metastatic spread, features mainly attributable to cancer stem cells (CSCs). It is of central interest the characterization of CSCs and, in particular, the study of their metabolic features in order to selectively identify their peculiarities for an efficient therapeutic approach. In this study, CSCs have been obtained by culturing different PDAC cell lines with a specific growth medium. Cells were characterized for the typical stem/mesenchymal properties at short-, medium-, and long-term culture. Metabolomics, proteomics, analysis of oxygen consumption rate in live cells, and the effect of the inhibition of lactate transporter on cell proliferation have been performed to delineate the metabolism of CSCs. We show that gradually de-differentiated pancreatic cancer cells progressively increase the expression of both stem and epithelial-to-mesenchymal transition markers, shift their metabolism from a glycolytic to an oxidative one, and lastly gain a quiescent state. These quiescent stem cells are characterized by high chemo-resistance, clonogenic ability, and metastatic potential. Re-differentiation reverts these features, re-activating their proliferative capacity and glycolytic metabolism, which generally correlates with high aggressiveness. These observations add an important piece of knowledge to the comprehension of the biology of CSCs, whose metabolic plasticity could be exploited for the generation of promising and selective therapeutic approaches for PDAC patients. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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14 pages, 3139 KiB

Open AccessArticle

Deferiprone (DFP) Targets Cancer Stem Cell (CSC) Propagation by Inhibiting Mitochondrial Metabolism and Inducing ROS Production

by Marco Fiorillo, Fanni Tóth, Matteo Brindisi, Federica Sotgia and Michael P. Lisanti

Cells 2020, 9(6), 1529; https://doi.org/10.3390/cells9061529 - 23 Jun 2020

Cited by 37 | Viewed by 6218

Abstract

Deferiprone (DFP), also known as Ferriprox, is an FDA-approved, orally active, iron chelator that is currently used clinically for the treatment of iron-overload, especially in thalassaemia major. As iron is a critical factor in Fe-S cluster assembly that is absolutely required for the [...] Read more.

Deferiprone (DFP), also known as Ferriprox, is an FDA-approved, orally active, iron chelator that is currently used clinically for the treatment of iron-overload, especially in thalassaemia major. As iron is a critical factor in Fe-S cluster assembly that is absolutely required for the metabolic function of mitochondria, we hypothesized that DFP treatment could be used to selectively target mitochondria in cancer stem cells (CSCs). For this purpose, we used two ER(+) human breast cancer cell lines, namely MCF7 and T47D cells, as model systems. More specifically, a 3D tumorsphere assay was employed as a functional readout of CSC activity which measures anchorage-independent growth under low attachment conditions. Here, we show that DFP dose dependently inhibited the propagation of CSCs, with an IC-50 of ~100 nM for MCF7 and an IC-50 of ~0.5 to 1 μM for T47D cells, making DFP one the most potent FDA-approved drugs that we and others have thus far identified for targeting CSCs. Mechanistically, we show that high concentrations of DFP metabolically targeted both mitochondrial oxygen consumption (OCR) and glycolysis (extracellular acidification rates (ECAR)) in MCF7 and T47D cell monolayers. Most importantly, we demonstrate that DFP also induced a generalized increase in reactive oxygen species (ROS) and mitochondrial superoxide production, and its effects reverted in the presence of N-acetyl-cysteine (NAC). Therefore, we propose that DFP is a new candidate therapeutic for drug repurposing and for Phase II clinical trials aimed at eradicating CSCs. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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18 pages, 5085 KiB

Open AccessArticle

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

by Vera Miranda-Gonçalves, Ana Lameirinhas, Catarina Macedo-Silva, João Lobo, Paula C. Dias, Verónica Ferreira, Rui Henrique and Carmen Jerónimo

Cells 2020, 9(4), 1053; https://doi.org/10.3390/cells9041053 - 23 Apr 2020

Cited by 31 | Viewed by 4276

Abstract

Background: Renal cell carcinoma (RCC) displays a glycolytic phenotype (Warburg effect). Increased lactate production, impacting on tumor biology and microenvironment modulation, has been implicated in epigenetic mechanisms’ regulation, leading to histone deacetylases inhibition. Thus, in-depth knowledge of lactate’s impact on epigenome regulation of [...] Read more.

Background: Renal cell carcinoma (RCC) displays a glycolytic phenotype (Warburg effect). Increased lactate production, impacting on tumor biology and microenvironment modulation, has been implicated in epigenetic mechanisms’ regulation, leading to histone deacetylases inhibition. Thus, in-depth knowledge of lactate’s impact on epigenome regulation of highly glycolytic tumors might allow for new therapeutic strategies. Herein, we investigated how extracellular lactate affected sirtuin 1 activity, a class III histone deacetylase (sirtuins, SIRTs) in RCC. Methods: In vitro and in vivo interactions between lactate and SIRT1 in RCC were investigated in normal kidney and RCC cell lines. Finally, SIRT1 and N-cadherin immunoexpression was assessed in human RCC and normal renal tissues. Results: Lactate inhibited SIRT1 expression in normal kidney and RCC cells, increasing global H3 and H3K9 acetylation. Cells exposed to lactate showed increased cell migration and invasion entailing a mesenchymal phenotype. Treatment with a SIRT1 inhibitor, nicotinamide (NAM), paralleled lactate effects, promoting cell aggressiveness. In contrast, alpha-cyano-4-hydroxycinnamate (CHC), a lactate transporter inhibitor, reversed them by blocking lactate transport. In vivo (chick chorioallantoic membrane (CAM) assay), lactate and NAM exposure were associated with increased tumor size and blood vessel recruitment, whereas CHC displayed the opposite effect. Moreover, primary RCC revealed N-cadherin upregulation whereas SIRT1 expression levels were downregulated compared to normal tissues. Conclusions: In RCC, lactate enhanced aggressiveness and modulated normal kidney cell phenotype, in part through downregulation of SIRT1, unveiling tumor metabolism as a promising therapeutic target. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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22 pages, 8756 KiB

Open AccessArticle

Glucose Metabolic Reprogramming of ER Breast Cancer in Acquired Resistance to the CDK4/6 Inhibitor Palbociclib⁺

by Nicla Lorito, Marina Bacci, Alfredo Smiriglia, Michele Mannelli, Matteo Parri, Giuseppina Comito, Luigi Ippolito, Elisa Giannoni, Martina Bonechi, Matteo Benelli, Ilenia Migliaccio, Luca Malorni, Paola Chiarugi and Andrea Morandi

Cells 2020, 9(3), 668; https://doi.org/10.3390/cells9030668 - 10 Mar 2020

Cited by 24 | Viewed by 5799

Abstract

The majority of breast cancers express the estrogen receptor (ER) and are dependent on estrogen for their growth and survival. Endocrine therapy (ET) is the standard of care for these tumors. However, a superior outcome is achieved in a subset of ER positive [...] Read more.

The majority of breast cancers express the estrogen receptor (ER) and are dependent on estrogen for their growth and survival. Endocrine therapy (ET) is the standard of care for these tumors. However, a superior outcome is achieved in a subset of ER positive (ER⁺)/human epidermal growth factor receptor 2 negative (HER2⁻) metastatic breast cancer patients when ET is administrated in combination with a cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor, such as palbociclib. Moreover, CDK4/6 inhibitors are currently being tested in ER⁺/HER2⁺ breast cancer and reported encouraging results. Despite the clinical advances of a combinatorial therapy using ET plus CDK4/6 inhibitors, potential limitations (i.e., resistance) could emerge and the metabolic adaptations underlying such resistance warrant further elucidation. Here we investigate the glucose-dependent catabolism in a series of isogenic ER⁺ breast cancer cell lines sensitive to palbociclib and in their derivatives with acquired resistance to the drug. Importantly, ER⁺/HER2⁻ and ER⁺/HER2⁺ cell lines show a different degree of glucose dependency. While ER⁺/HER2⁻ breast cancer cells are characterized by enhanced aerobic glycolysis at the time of palbociclib sensitivity, ER⁺/HER2⁺ cells enhance their glycolytic catabolism at resistance. This metabolic phenotype was shown to have prognostic value and was targeted with multiple approaches offering a series of potential scenarios that could be of clinical relevance. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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Review

Jump to: Editorial, Research

33 pages, 2912 KiB

Open AccessReview

The Role of Mitochondria in the Chemoresistance of Pancreatic Cancer Cells

by Yibo Fu, Francesca Ricciardiello, Gang Yang, Jiangdong Qiu, Hua Huang, Jianchun Xiao, Zhe Cao, Fangyu Zhao, Yueze Liu, Wenhao Luo, Guangyu Chen, Lei You, Ferdinando Chiaradonna, Lianfang Zheng and Taiping Zhang

Cells 2021, 10(3), 497; https://doi.org/10.3390/cells10030497 - 25 Feb 2021

Cited by 29 | Viewed by 5379

Abstract

The first-line chemotherapies for patients with unresectable pancreatic cancer (PC) are 5-fluorouracil (5-FU) and gemcitabine therapy. However, due to chemoresistance the prognosis of patients with PC has not been significantly improved. Mitochondria are essential organelles in eukaryotes that evolved from aerobic bacteria. In [...] Read more.

The first-line chemotherapies for patients with unresectable pancreatic cancer (PC) are 5-fluorouracil (5-FU) and gemcitabine therapy. However, due to chemoresistance the prognosis of patients with PC has not been significantly improved. Mitochondria are essential organelles in eukaryotes that evolved from aerobic bacteria. In recent years, many studies have shown that mitochondria play important roles in tumorigenesis and may act as chemotherapeutic targets in PC. In addition, according to recent studies, mitochondria may play important roles in the chemoresistance of PC by affecting apoptosis, metabolism, mtDNA metabolism, and mitochondrial dynamics. Interfering with some of these factors in mitochondria may improve the sensitivity of PC cells to chemotherapeutic agents, such as gemcitabine, making mitochondria promising targets for overcoming chemoresistance in PC. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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17 pages, 1403 KiB

Open AccessFeature PaperReview

Iron Metabolism in the Tumor Microenvironment—Implications for Anti-Cancer Immune Response

by Alessandro Sacco, Anna Martina Battaglia, Cirino Botta, Ilenia Aversa, Serafina Mancuso, Francesco Costanzo and Flavia Biamonte

Cells 2021, 10(2), 303; https://doi.org/10.3390/cells10020303 - 2 Feb 2021

Cited by 62 | Viewed by 7552

Abstract

New insights into the field of iron metabolism within the tumor microenvironment have been uncovered in recent years. Iron promotes the production of reactive oxygen species, which may either trigger ferroptosis cell death or contribute to malignant transformation. Once transformed, cancer cells divert [...] Read more.

New insights into the field of iron metabolism within the tumor microenvironment have been uncovered in recent years. Iron promotes the production of reactive oxygen species, which may either trigger ferroptosis cell death or contribute to malignant transformation. Once transformed, cancer cells divert tumor-infiltrating immune cells to satisfy their iron demand, thus affecting the tumor immunosurveillance. In this review, we highlight how the bioavailability of this metal shapes complex metabolic pathways within the tumor microenvironment and how this affects both tumor-associated macrophages and tumor-infiltrating lymphocytes functions. Furthermore, we discuss the potentials as well as the current clinical controversies surrounding the use of iron metabolism as a target for new anticancer treatments in two opposed conditions: (i) the “hot” tumors, which are usually enriched in immune cells infiltration and are extremely rich in iron availability within the microenvironment, and (ii) the “cold” tumors, which are often very poor in immune cells, mainly due to immune exclusion. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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16 pages, 2877 KiB

Open AccessReview

Manipulating the Metabolism to Improve the Efficacy of CAR T-Cell Immunotherapy

by Marsha Pellegrino, Francesca Del Bufalo, Biagio De Angelis, Concetta Quintarelli, Ignazio Caruana and Emmanuel de Billy

Cells 2021, 10(1), 14; https://doi.org/10.3390/cells10010014 - 24 Dec 2020

Cited by 33 | Viewed by 8633

Abstract

The adoptive transfer of the chimeric antigen receptor (CAR) expressing T-cells has produced unprecedented successful results in the treatment of B-cell malignancies. However, the use of this technology in other malignancies remains less effective. In the setting of solid neoplasms, CAR T-cell metabolic [...] Read more.

The adoptive transfer of the chimeric antigen receptor (CAR) expressing T-cells has produced unprecedented successful results in the treatment of B-cell malignancies. However, the use of this technology in other malignancies remains less effective. In the setting of solid neoplasms, CAR T-cell metabolic fitness needs to be optimal to reach the tumor and execute their cytolytic function in an environment often hostile. It is now well established that both tumor and T cell metabolisms play critical roles in controlling the immune response by conditioning the tumor microenvironment and the fate and activity of the T cells. In this review, after a brief description of the tumoral and T cell metabolic reprogramming, we summarize the latest advances and new strategies that have been developed to improve the metabolic fitness and efficacy of CAR T-cell products. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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17 pages, 424 KiB

Open AccessReview

Fructose Metabolism in Cancer

by Nils Krause and Andre Wegner

Cells 2020, 9(12), 2635; https://doi.org/10.3390/cells9122635 - 8 Dec 2020

Cited by 48 | Viewed by 13801

Abstract

The interest in fructose metabolism is based on the observation that an increased dietary fructose consumption leads to an increased risk of obesity and metabolic syndrome. In particular, obesity is a known risk factor to develop many types of cancer and there is [...] Read more.

The interest in fructose metabolism is based on the observation that an increased dietary fructose consumption leads to an increased risk of obesity and metabolic syndrome. In particular, obesity is a known risk factor to develop many types of cancer and there is clinical and experimental evidence that an increased fructose intake promotes cancer growth. The precise mechanism, however, in which fructose induces tumor growth is still not fully understood. In this article, we present an overview of the metabolic pathways that utilize fructose and how fructose metabolism can sustain cancer cell proliferation. Although the degradation of fructose shares many of the enzymes and metabolic intermediates with glucose metabolism through glycolysis, glucose and fructose are metabolized differently. We describe the different metabolic fates of fructose carbons and how they are connected to lipogenesis and nucleotide synthesis. In addition, we discuss how the endogenous production of fructose from glucose via the polyol pathway can be beneficial for cancer cells. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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29 pages, 1403 KiB

Open AccessReview

Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance

by Dimas Carolina Belisario, Joanna Kopecka, Martina Pasino, Muhlis Akman, Enrico De Smaele, Massimo Donadelli and Chiara Riganti

Cells 2020, 9(12), 2598; https://doi.org/10.3390/cells9122598 - 4 Dec 2020

Cited by 71 | Viewed by 6265

Abstract

Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favor [...] Read more.

Hypoxia is a condition commonly observed in the core of solid tumors. The hypoxia-inducible factors (HIF) act as hypoxia sensors that orchestrate a coordinated response increasing the pro-survival and pro-invasive phenotype of cancer cells, and determine a broad metabolic rewiring. These events favor tumor progression and chemoresistance. The increase in glucose and amino acid uptake, glycolytic flux, and lactate production; the alterations in glutamine metabolism, tricarboxylic acid cycle, and oxidative phosphorylation; the high levels of mitochondrial reactive oxygen species; the modulation of both fatty acid synthesis and oxidation are hallmarks of the metabolic rewiring induced by hypoxia. This review discusses how metabolic-dependent factors (e.g., increased acidification of tumor microenvironment coupled with intracellular alkalinization, and reduced mitochondrial metabolism), and metabolic-independent factors (e.g., increased expression of drug efflux transporters, stemness maintenance, and epithelial-mesenchymal transition) cooperate in determining chemoresistance in hypoxia. Specific metabolic modifiers, however, can reverse the metabolic phenotype of hypoxic tumor areas that are more chemoresistant into the phenotype typical of chemosensitive cells. We propose these metabolic modifiers, able to reverse the hypoxia-induced metabolic rewiring, as potential chemosensitizer agents against hypoxic and refractory tumor cells. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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28 pages, 1159 KiB

Open AccessReview

Iron: An Essential Element of Cancer Metabolism

by Myriam Y. Hsu, Erica Mina, Antonella Roetto and Paolo E. Porporato

Cells 2020, 9(12), 2591; https://doi.org/10.3390/cells9122591 - 3 Dec 2020

Cited by 69 | Viewed by 7630

Abstract

Cancer cells undergo considerable metabolic changes to foster uncontrolled proliferation in a hostile environment characterized by nutrient deprivation, poor vascularization and immune infiltration. While metabolic reprogramming has been recognized as a hallmark of cancer, the role of micronutrients in shaping these adaptations remains [...] Read more.

Cancer cells undergo considerable metabolic changes to foster uncontrolled proliferation in a hostile environment characterized by nutrient deprivation, poor vascularization and immune infiltration. While metabolic reprogramming has been recognized as a hallmark of cancer, the role of micronutrients in shaping these adaptations remains scarcely investigated. In particular, the broad electron-transferring abilities of iron make it a versatile cofactor that is involved in a myriad of biochemical reactions vital to cellular homeostasis, including cell respiration and DNA replication. In cancer patients, systemic iron metabolism is commonly altered. Moreover, cancer cells deploy diverse mechanisms to increase iron bioavailability to fuel tumor growth. Although iron itself can readily participate in redox reactions enabling vital processes, its reactivity also gives rise to reactive oxygen species (ROS). Hence, cancer cells further rely on antioxidant mechanisms to withstand such stress. The present review provides an overview of the common alterations of iron metabolism occurring in cancer and the mechanisms through which iron promotes tumor growth. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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17 pages, 1685 KiB

Open AccessReview

FTH1 Pseudogenes in Cancer and Cell Metabolism

by Maddalena Di Sanzo, Barbara Quaresima, Flavia Biamonte, Camillo Palmieri and Maria Concetta Faniello

Cells 2020, 9(12), 2554; https://doi.org/10.3390/cells9122554 - 28 Nov 2020

Cited by 34 | Viewed by 5297

Abstract

Ferritin, the principal intracellular iron-storage protein localized in the cytoplasm, nucleus, and mitochondria, plays a major role in iron metabolism. The encoding ferritin genes are members of a multigene family that includes some pseudogenes. Even though pseudogenes have been initially considered as relics [...] Read more.

Ferritin, the principal intracellular iron-storage protein localized in the cytoplasm, nucleus, and mitochondria, plays a major role in iron metabolism. The encoding ferritin genes are members of a multigene family that includes some pseudogenes. Even though pseudogenes have been initially considered as relics of ancient genes or junk DNA devoid of function, their role in controlling gene expression in normal and transformed cells has recently been re-evaluated. Numerous studies have revealed that some pseudogenes compete with their parental gene for binding to the microRNAs (miRNAs), while others generate small interference RNAs (siRNAs) to decrease functional gene expression, and still others encode functional mutated proteins. Consequently, pseudogenes can be considered as actual master regulators of numerous biological processes. Here, we provide a detailed classification and description of the structural features of the ferritin pseudogenes known to date and review the recent evidence on their mutual interrelation within the complex regulatory network of the ferritin gene family. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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26 pages, 1190 KiB

Open AccessReview

“The Loss of Golden Touch”: Mitochondria-Organelle Interactions, Metabolism, and Cancer

by Matteo Audano, Silvia Pedretti, Simona Ligorio, Maurizio Crestani, Donatella Caruso, Emma De Fabiani and Nico Mitro

Cells 2020, 9(11), 2519; https://doi.org/10.3390/cells9112519 - 21 Nov 2020

Cited by 18 | Viewed by 5352

Abstract

Mitochondria represent the energy hub of cells and their function is under the constant influence of their tethering with other subcellular organelles. Mitochondria interact with the endoplasmic reticulum, lysosomes, cytoskeleton, peroxisomes, and nucleus in several ways, ranging from signal transduction, vesicle transport, and [...] Read more.

Mitochondria represent the energy hub of cells and their function is under the constant influence of their tethering with other subcellular organelles. Mitochondria interact with the endoplasmic reticulum, lysosomes, cytoskeleton, peroxisomes, and nucleus in several ways, ranging from signal transduction, vesicle transport, and membrane contact sites, to regulate energy metabolism, biosynthetic processes, apoptosis, and cell turnover. Tumorigenesis is often associated with mitochondrial dysfunction, which could likely be the result of an altered interaction with different cell organelles or structures. The purpose of the present review is to provide an updated overview of the links between inter-organellar communications and interactions and metabolism in cancer cells, with a focus on mitochondria. The very recent publication of several reviews on these aspects testifies the great interest in the area. Here, we aim at (1) summarizing recent evidence supporting that the metabolic rewiring and adaptation observed in tumors deeply affect organelle dynamics and cellular functions and vice versa; (2) discussing insights on the underlying mechanisms, when available; and (3) critically presenting the gaps in the field that need to be filled, for a comprehensive understanding of tumor cells’ biology. Chemo-resistance and druggable vulnerabilities of cancer cells related to the aspects mentioned above is also outlined. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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25 pages, 1196 KiB

Open AccessReview

Metformin: Metabolic Rewiring Faces Tumor Heterogeneity

by Mario Cioce, Claudio Pulito, Sabrina Strano, Giovanni Blandino and Vito Michele Fazio

Cells 2020, 9(11), 2439; https://doi.org/10.3390/cells9112439 - 9 Nov 2020

Cited by 25 | Viewed by 5989

Abstract

Tumor heterogeneity impinges on all the aspects of tumor history, from onset to metastasis and relapse. It is growingly recognized as a propelling force for tumor adaptation to environmental and micro-environmental cues. Metabolic heterogeneity perfectly falls into this process. It strongly contributes to [...] Read more.

Tumor heterogeneity impinges on all the aspects of tumor history, from onset to metastasis and relapse. It is growingly recognized as a propelling force for tumor adaptation to environmental and micro-environmental cues. Metabolic heterogeneity perfectly falls into this process. It strongly contributes to the metabolic plasticity which characterizes cancer cell subpopulations—capable of adaptive switching under stress conditions, between aerobic glycolysis and oxidative phosphorylation—in both a convergent and divergent modality. The mitochondria appear at center-stage in this adaptive process and thus, targeting mitochondria in cancer may prove of therapeutic value. Metformin is the oldest and most used anti-diabetic medication and its relationship with cancer has witnessed rises and falls in the last 30 years. We believe it is useful to revisit the main mechanisms of action of metformin in light of the emerging views on tumor heterogeneity. We first analyze the most consolidated view of its mitochondrial mechanism of action and then we frame the latter in the context of tumor adaptive strategies, cancer stem cell selection, metabolic zonation of tumors and the tumor microenvironment. This may provide a more critical point of view and, to some extent, may help to shed light on some of the controversial evidence for metformin’s anticancer action. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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32 pages, 1475 KiB

Open AccessFeature PaperReview

Metabolic Constrains Rule Metastasis Progression

by Niccolo’ Roda, Valentina Gambino and Marco Giorgio

Cells 2020, 9(9), 2081; https://doi.org/10.3390/cells9092081 - 11 Sep 2020

Cited by 15 | Viewed by 4043

Abstract

Metastasis formation accounts for the majority of tumor-associated deaths and consists of different steps, each of them being characterized by a distinctive adaptive phenotype of the cancer cells. Metabolic reprogramming represents one of the main adaptive phenotypes exploited by cancer cells during all [...] Read more.

Metastasis formation accounts for the majority of tumor-associated deaths and consists of different steps, each of them being characterized by a distinctive adaptive phenotype of the cancer cells. Metabolic reprogramming represents one of the main adaptive phenotypes exploited by cancer cells during all the main steps of tumor and metastatic progression. In particular, the metabolism of cancer cells evolves profoundly through all the main phases of metastasis formation, namely the metastatic dissemination, the metastatic colonization of distant organs, the metastatic dormancy, and ultimately the outgrowth into macroscopic lesions. However, the metabolic reprogramming of metastasizing cancer cells has only recently become the subject of intense study. From a clinical point of view, the latter steps of the metastatic process are very important, because patients often undergo surgical removal of the primary tumor when cancer cells have already left the primary tumor site, even though distant metastases are not clinically detectable yet. In this scenario, to precisely elucidate if and how metabolic reprogramming drives acquisition of cancer-specific adaptive phenotypes might pave the way to new therapeutic strategies by combining chemotherapy with metabolic drugs for better cancer eradication. In this review we discuss the latest evidence that claim the importance of metabolic adaptation for cancer progression. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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25 pages, 1991 KiB

Open AccessReview

Metabolic Potential of Cancer Cells in Context of the Metastatic Cascade

by Mohaned Benzarti, Catherine Delbrouck, Laura Neises, Nicole Kiweler and Johannes Meiser

Cells 2020, 9(9), 2035; https://doi.org/10.3390/cells9092035 - 5 Sep 2020

Cited by 13 | Viewed by 5135

Abstract

The metastatic cascade is a highly plastic and dynamic process dominated by cellular heterogeneity and varying metabolic requirements. During this cascade, the three major metabolic pillars, namely biosynthesis, RedOx balance, and bioenergetics, have variable importance. Biosynthesis has superior significance during the proliferation-dominated steps [...] Read more.

The metastatic cascade is a highly plastic and dynamic process dominated by cellular heterogeneity and varying metabolic requirements. During this cascade, the three major metabolic pillars, namely biosynthesis, RedOx balance, and bioenergetics, have variable importance. Biosynthesis has superior significance during the proliferation-dominated steps of primary tumour growth and secondary macrometastasis formation and only minor relevance during the growth-independent processes of invasion and dissemination. Consequently, RedOx homeostasis and bioenergetics emerge as conceivable metabolic key determinants in cancer cells that disseminate from the primary tumour. Within this review, we summarise our current understanding on how cancer cells adjust their metabolism in the context of different microenvironments along the metastatic cascade. With the example of one-carbon metabolism, we establish a conceptual view on how the same metabolic pathway can be exploited in different ways depending on the current cellular needs during metastatic progression. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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29 pages, 1462 KiB

Open AccessReview

Membrane Transporters for Amino Acids as Players of Cancer Metabolic Rewiring

by Mariafrancesca Scalise, Lara Console, Filomena Rovella, Michele Galluccio, Lorena Pochini and Cesare Indiveri

Cells 2020, 9(9), 2028; https://doi.org/10.3390/cells9092028 - 3 Sep 2020

Cited by 32 | Viewed by 6403

Abstract

Cancer cells perform a metabolic rewiring to sustain an increased growth rate and compensate for the redox stress caused by augmented energy metabolism. The metabolic changes are not the same in all cancers. Some features, however, are considered hallmarks of this disease. As [...] Read more.

Cancer cells perform a metabolic rewiring to sustain an increased growth rate and compensate for the redox stress caused by augmented energy metabolism. The metabolic changes are not the same in all cancers. Some features, however, are considered hallmarks of this disease. As an example, all cancer cells rewire the amino acid metabolism for fulfilling both the energy demand and the changed signaling routes. In these altered conditions, some amino acids are more frequently used than others. In any case, the prerequisite for amino acid utilization is the presence of specific transporters in the cell membrane that can guarantee the absorption and the traffic of amino acids among tissues. Tumor cells preferentially use some of these transporters for satisfying their needs. The evidence for this phenomenon is the over-expression of selected transporters, associated with specific cancer types. The knowledge of the link between the over-expression and the metabolic rewiring is crucial for understanding the molecular mechanism of reprogramming in cancer cells. The continuous growth of information on structure–function relationships and the regulation of transporters will open novel perspectives in the fight against human cancers. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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30 pages, 2612 KiB

Open AccessReview

Breast Cancer Chemotherapeutic Options: A General Overview on the Preclinical Validation of a Multi-Target Ruthenium(III) Complex Lodged in Nucleolipid Nanosystems

by Maria Grazia Ferraro, Marialuisa Piccolo, Gabriella Misso, Francesco Maione, Daniela Montesarchio, Michele Caraglia, Luigi Paduano, Rita Santamaria and Carlo Irace

Cells 2020, 9(6), 1412; https://doi.org/10.3390/cells9061412 - 5 Jun 2020

Cited by 26 | Viewed by 3593

Abstract

In this review we have showcased the preclinical development of original amphiphilic nanomaterials designed for ruthenium-based anticancer treatments, to be placed within the current metallodrugs approach leading over the past decade to advanced multitarget agents endowed with limited toxicity and resistance. This strategy [...] Read more.

In this review we have showcased the preclinical development of original amphiphilic nanomaterials designed for ruthenium-based anticancer treatments, to be placed within the current metallodrugs approach leading over the past decade to advanced multitarget agents endowed with limited toxicity and resistance. This strategy could allow for new options for breast cancer (BC) interventions, including the triple-negative subtype (TNBC) with poor therapeutic alternatives. BC is currently the second most widespread cancer and the primary cause of cancer death in women. Hence, the availability of novel chemotherapeutic weapons is a basic requirement to fight BC subtypes. Anticancer drugs based on ruthenium are among the most explored and advanced next-generation metallotherapeutics, with NAMI-A and KP1019 as two iconic ruthenium complexes having undergone clinical trials. In addition, many nanomaterial Ru complexes have been recently conceived and developed into anticancer drugs demonstrating attractive properties. In this field, we focused on the evaluation of a Ru(III) complex—named AziRu—incorporated into a suite of both zwitterionic and cationic nucleolipid nanosystems, which proved to be very effective for the in vivo targeting of breast cancer cells (BBC). Mechanisms of action have been widely explored in the context of preclinical evaluations in vitro, highlighting a multitarget action on cell death pathways which are typically deregulated in neoplasms onset and progression. Moreover, being AziRu inspired by the well-known NAMI-A complex, information on non-nanostructured Ru-based anticancer agents have been included in a precise manner. Full article

(This article belongs to the Special Issue Metabolic Rewiring in Cancer Cells: From Tumor Onset to Novel Therapies)

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