Dexfenfluramine and Pergolide Cause Heart Valve Disease via Valve Metabolic Reprogramming and Ongoing Matrix Remodeling

Several clinical reports indicate that the use of amphetaminic anorectic drugs or ergot derivatives could cause valvular heart disease (VHD). We sought to investigate whether valvular lesions develop in response to long-term oral administration of these drugs and to identify drug-targeted biological processes that may lead to VHD. Treatment of New Zealand White rabbits with pergolide, dexfenfluramine, or high-dose serotonin for 16 weeks induced valvular alterations characterized by extracellular matrix remodeling. Transcriptome profiling of tricuspid valves using RNA sequencing revealed distinct patterns of differentially expressed genes (DEGs) that clustered according to the different treatments. Genes that were affected by the three treatments were functionally enriched for reduced cell metabolism processes. The two drugs yielded more changes in gene expression than serotonin and shared most of the DEGs. These DEGs were mostly enriched for decreased biosynthetic processes, increased cell-matrix interaction, and cell response to growth factors, including TGF-β, which was associated with p38 MAPK activation. Treatment with pergolide specifically affected genes involved in homeostasis, which was corroborated by the activation of the master regulator of cell energy homeostasis, AMPK-α, as well as decreased levels of metabolism-related miR-107. Thus, both pergolide and dexfenfluramine may cause VHD through valve metabolic reprogramming and matrix remodeling.

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AMPK promotes induction of a tumor suppressor FLCN through activation of TFEB independently of mTOR

10.1101/499921 ◽

2018 ◽

Author(s):

Caterina Collodet ◽

Marc Foretz ◽

Maria Deak ◽

Laurent Bultot ◽

Sylviane Metairon ◽

...

Keyword(s):

Gene Expression ◽

Tumor Suppressor ◽

Energy Homeostasis ◽

Transcriptome Profiling ◽

Metabolic Reprogramming ◽

Double Knockout ◽

Transcription Factor Eb ◽

Pathway Analyses ◽

Amp Activated Protein Kinase

AMP-activated protein kinase (AMPK) is a central energy sensor and master regulator of energy homeostasis. AMPK not only elicits acute metabolic responses, but also promotes metabolic reprogramming and adaptions in the long-term through regulation of specific transcription factors/co-activators. We performed a whole-genome transcriptome profiling in wild-type and AMPK-deficient mouse embryonic fibroblasts (MEF) and primary hepatocytes that had been treated with two distinct classes of small-molecule AMPK activators, namely 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) or 991. This led to the identification of distinct compound-dependent gene expression signatures and to the discovery of several AMPK-regulated genes, including Flcn encoding a tumor suppressor and nutrient sensor folliculin (FLCN). Gene set enrichment and pathway analyses identified the lysosomal pathway and the associated transcription factor EB (TFEB) as key transcriptional mediator responsible for AMPK-dependent gene expression changes. AMPK-induced Flcn expression was abolished in TFEB/TFE3 double knockout MEF and the promoter activity of Flcn was profoundly reduced when its putative TFEB-binding site was mutated. Mechanistically, we have found that AMPK promotes the dephosphorylation and nuclear localization of TFEB independently of mTOR activity. Collectively, we identified the AMPK-TFEB-FLCN axis as a potential key regulator for cellular and metabolic homeostasis. Moreover, data from zebrafish with physiologically and pharmacologically activated AMPK supports the existence of the AMPK-TFEB-FLCN cascade in vivo.

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DDR1 Affects Metabolic Reprogramming in Breast Cancer Cells by Cross-Talking to the Insulin/IGF System

Biomolecules ◽

10.3390/biom11070926 ◽

2021 ◽

Vol 11 (7) ◽

pp. 926

Author(s):

Veronica Vella ◽

Marika Giuliano ◽

Maria Luisa Nicolosi ◽

Maria Giovanna Majorana ◽

Małgorzata Anna Marć ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Cells ◽

Cell Metabolism ◽

Growth Factor Receptor ◽

Metabolic Reprogramming ◽

Atp Production ◽

Igf System ◽

Putative Target ◽

Collagen Receptor ◽

Discoidin Domain Receptor 1

The insulin receptor isoform A (IR-A), a dual receptor for insulin and IGF2, plays a role in breast cancer (BC) progression and metabolic reprogramming. Notably, discoidin domain receptor 1 (DDR1), a collagen receptor often dysregulated in cancer, is involved in a functional crosstalk and feed forward loop with both the IR-A and the insulin like growth factor receptor 1 (IGF1R). Here, we aimed at investigating whether DDR1 might affect BC cell metabolism by modulating the IGF1R and/or the IR. To this aim, we generated MCF7 BC cells engineered to stably overexpress either IGF2 (MCF7/IGF2) or the IR-A (MCF7/IR-A). In both cell models, we observed that DDR1 silencing induced a significant decrease of total ATP production, particularly affecting the rate of mitochondrial ATP production. We also observed the downregulation of key molecules implicated in both glycolysis and oxidative phosphorylation. These metabolic changes were not modulated by DDR1 binding to collagen and occurred in part in the absence of IR/IGF1R phosphorylation. DDR1 silencing was ineffective in MCF7 knocked out for DDR1. Taken together, these results indicate that DDR1, acting in part independently of IR / IGF1R stimulation, might work as a novel regulator of BC metabolism and should be considered as putative target for therapy in BC.

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Metabolic Anti-Cancer Effects of Melatonin: Clinically Relevant Prospects

Cancers ◽

10.3390/cancers13123018 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3018

Author(s):

Marek Samec ◽

Alena Liskova ◽

Lenka Koklesova ◽

Kevin Zhai ◽

Elizabeth Varghese ◽

...

Keyword(s):

Cancer Metabolism ◽

Glucose Transporter ◽

Aerobic Glycolysis ◽

Cell Metabolism ◽

Lactate Production ◽

Pentose Phosphate ◽

Metabolic Reprogramming ◽

Effective Prevention ◽

Anti Cancer ◽

Glucose 6 Phosphate Dehydrogenase

Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers.

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The Dynamic Interaction between Extracellular Matrix Remodeling and Breast Tumor Progression

Cells ◽

10.3390/cells10051046 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1046

Author(s):

Jorge Martinez ◽

Patricio C. Smith

Keyword(s):

Extracellular Matrix ◽

Type I Collagen ◽

Cell Metabolism ◽

Breast Tumors ◽

Extracellular Matrix Remodeling ◽

Type I ◽

Matrix Remodeling ◽

Desmoplastic Reaction ◽

The Impact

Desmoplastic tumors correspond to a unique tissue structure characterized by the abnormal deposition of extracellular matrix. Breast tumors are a typical example of this type of lesion, a property that allows its palpation and early detection. Fibrillar type I collagen is a major component of tumor desmoplasia and its accumulation is causally linked to tumor cell survival and metastasis. For many years, the desmoplastic phenomenon was considered to be a reaction and response of the host tissue against tumor cells and, accordingly, designated as “desmoplastic reaction”. This notion has been challenged in the last decades when desmoplastic tissue was detected in breast tissue in the absence of tumor. This finding suggests that desmoplasia is a preexisting condition that stimulates the development of a malignant phenotype. With this perspective, in the present review, we analyze the role of extracellular matrix remodeling in the development of the desmoplastic response. Importantly, during the discussion, we also analyze the impact of obesity and cell metabolism as critical drivers of tissue remodeling during the development of desmoplasia. New knowledge derived from the dynamic remodeling of the extracellular matrix may lead to novel targets of interest for early diagnosis or therapy in the context of breast tumors.

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The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs

International Journal of Molecular Sciences ◽

10.3390/ijms22031171 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1171

Author(s):

Dexter L. Puckett ◽

Mohammed Alquraishi ◽

Winyoo Chowanadisai ◽

Ahmed Bettaieb

Keyword(s):

Cancer Cells ◽

Pyruvate Kinase ◽

Cancer Metabolism ◽

Cell Metabolism ◽

Metabolic Reprogramming ◽

Circular Rnas ◽

Tissue Specific ◽

Cell Progression ◽

Non Coding Rnas ◽

Regulatory Effects

Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance.

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The F1Fo-ATPase inhibitor, IF1, is a critical regulator of energy metabolism in cancer cells

Biochemical Society Transactions ◽

10.1042/bst20200742 ◽

2021 ◽

Vol 49 (2) ◽

pp. 815-827

Author(s):

Giancarlo Solaini ◽

Gianluca Sgarbi ◽

Alessandra Baracca

Keyword(s):

Cancer Cells ◽

Atp Synthase ◽

Aerobic Glycolysis ◽

Cell Metabolism ◽

Metabolic Reprogramming ◽

Endogenous Inhibitor ◽

Atpase Inhibitor ◽

Molecular Action ◽

F1fo Atpase

In the last two decades, IF1, the endogenous inhibitor of the mitochondrial F1Fo-ATPase (ATP synthase) has assumed greater and ever greater interest since it has been found to be overexpressed in many cancers. At present, several findings indicate that IF1 is capable of playing a central role in cancer cells by promoting metabolic reprogramming, proliferation and resistance to cell death. However, the mechanism(s) at the basis of this pro-oncogenic action of IF1 remains elusive. Here, we recall the main features of the mechanism of the action of IF1 when the ATP synthase works in reverse, and discuss the experimental evidence that support its relevance in cancer cells. In particular, a clear pro-oncogenic action of IF1 is to avoid wasting of ATP when cancer cells are exposed to anoxia or near anoxia conditions, therefore favoring cell survival and tumor growth. However, more recently, various papers have described IF1 as an inhibitor of the ATP synthase when it is working physiologically (i.e. synthethizing ATP), and therefore reprogramming cell metabolism to aerobic glycolysis. In contrast, other studies excluded IF1 as an inhibitor of ATP synthase under normoxia, providing the basis for a hot debate. This review focuses on the role of IF1 as a modulator of the ATP synthase in normoxic cancer cells with the awareness that the knowledge of the molecular action of IF1 on the ATP synthase is crucial in unravelling the molecular mechanism(s) responsible for the pro-oncogenic role of IF1 in cancer and in developing related anticancer strategies.

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The Development of Single-Cell Metabolism and Its Role in Studying Cancer Emergent Properties

Frontiers in Oncology ◽

10.3389/fonc.2021.814085 ◽

2022 ◽

Vol 11 ◽

Author(s):

Dingju Wei ◽

Meng Xu ◽

Zhihua Wang ◽

Jingjing Tong

Keyword(s):

Tumor Cell ◽

Single Cell ◽

Immune Escape ◽

Cell Metabolism ◽

Single Cells ◽

Metabolic Reprogramming ◽

Biological Information ◽

Emergent Properties ◽

Anti Cancer ◽

Cell Metabolomics

Metabolic reprogramming is one of the hallmarks of malignant tumors, which provides energy and material basis for tumor rapid proliferation, immune escape, as well as extensive invasion and metastasis. Blocking the energy and material supply of tumor cells is one of the strategies to treat tumor, however tumor cell metabolic heterogeneity prevents metabolic-based anti-cancer treatment. Therefore, searching for the key metabolic factors that regulate cell cancerous change and tumor recurrence has become a major challenge. Emerging technology––single-cell metabolomics is different from the traditional metabolomics that obtains average information of a group of cells. Single-cell metabolomics identifies the metabolites of single cells in different states by mass spectrometry, and captures the molecular biological information of the energy and substances synthesized in single cells, which provides more detailed information for tumor treatment metabolic target screening. This review will combine the current research status of tumor cell metabolism with the advantages of single-cell metabolomics technology, and explore the role of single-cell sequencing technology in searching key factors regulating tumor metabolism. The addition of single-cell technology will accelerate the development of metabolism-based anti-cancer strategies, which may greatly improve the prognostic survival rate of cancer patients.

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KSHV Reprogramming of Host Energy Metabolism for Pathogenesis

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.621156 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaoqing Liu ◽

Caixia Zhu ◽

Yuyan Wang ◽

Fang Wei ◽

Qiliang Cai

Keyword(s):

Energy Metabolism ◽

Metabolic Pathways ◽

B Lymphocyte ◽

Aerobic Glycolysis ◽

Cell Metabolism ◽

Acid Synthesis ◽

Central Carbon Metabolism ◽

Central Carbon ◽

Cell Energy ◽

Infected Cells

Reprogramming of energy metabolism is a key for cancer development. Kaposi’s sarcoma-associated herpesvirus (KSHV), a human oncogenic herpesvirus, is tightly associated with several human malignancies by infecting B-lymphocyte or endothelial cells. Cancer cell energy metabolism is mainly dominated by three pathways of central carbon metabolism, including aerobic glycolysis, glutaminolysis, and fatty acid synthesis. Increasing evidence has shown that KSHV infection can alter central carbon metabolic pathways to produce biomass for viral replication, as well as the survival and proliferation of infected cells. In this review, we summarize recent studies exploring how KSHV manipulates host cell metabolism to promote viral pathogenesis, which provides the potential therapeutic targets and strategies for KSHV-associated cancers.

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The Neglected Liaison: Targeting Cancer Cell Metabolic Reprogramming Modifies the Composition of Non-Malignant Populations of the Tumor Microenvironment

Cancers ◽

10.3390/cancers13215447 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5447

Author(s):

Maria Iorio ◽

Nikkitha Umesh Ganesh ◽

Monica De Luise ◽

Anna Maria Porcelli ◽

Giuseppe Gasparre ◽

...

Keyword(s):

Complex System ◽

Clinical Trials ◽

Cancer Cell ◽

Immune Cells ◽

Cell Metabolism ◽

Metabolic Reprogramming ◽

Preclinical Studies ◽

Tumor Mass ◽

Cancer Cell Metabolism ◽

Target Cancer

Metabolic reprogramming is a well-known hallmark of cancer, whereby the development of drugs that target cancer cell metabolism is gaining momentum. However, when establishing preclinical studies and clinical trials, it is often neglected that a tumor mass is a complex system in which cancer cells coexist and interact with several types of microenvironment populations, including endothelial cells, fibroblasts and immune cells. We are just starting to understand how such populations are affected by the metabolic changes occurring in a transformed cell and little is known

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NRF2 as a regulator of cell metabolism and inflammation in cancer

Carcinogenesis ◽

10.1093/carcin/bgaa039 ◽

2020 ◽

Vol 41 (4) ◽

pp. 405-416 ◽

Cited By ~ 3

Author(s):

Feng He ◽

Laura Antonucci ◽

Michael Karin

Keyword(s):

Oxidative Stress ◽

Cancer Risk ◽

Poor Prognosis ◽

Cell Metabolism ◽

Transcriptional Regulator ◽

Negative Control ◽

Metabolic Reprogramming ◽

Related Factor ◽

Nuclear Factor ◽

Nrf2 Activation

Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) is a master transcriptional regulator of genes whose products defend our cells for toxic and oxidative insults. Although NRF2 activation may reduce cancer risk by suppressing oxidative stress and tumor-promoting inflammation, many cancers exhibit elevated NRF2 activity either due to mutations that disrupt the negative control of NRF2 activity or other factors. Importantly, NRF2 activation is associated with poor prognosis and NRF2 has turned out to be a key activator of cancer-supportive anabolic metabolism. In this review, we summarize the diverse roles played by NRF2 in cancer focusing on metabolic reprogramming and tumor-promoting inflammation.

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