Metabolic Reprogramming of Thyroid Cancer Cells and Crosstalk in Their Microenvironment

Metabolism differs significantly between tumor and normal cells. Metabolic reprogramming in cancer cells and metabolic interplay in the tumor microenvironment (TME) are important for tumor formation and progression. Tumor cells show changes in both catabolism and anabolism. Altered aerobic glycolysis, known as the Warburg effect, is a well-recognized characteristic of tumor cell energy metabolism. Compared with normal cells, tumor cells consume more glucose and glutamine. The enhanced anabolism in tumor cells includes de novo lipid synthesis as well as protein and nucleic acid synthesis. Although these forms of energy supply are uneconomical, they are required for the functioning of cancer cells, including those in thyroid cancer (TC). Increasing attention has recently focused on alterations of the TME. Understanding the metabolic changes governing the intricate relationship between TC cells and the TME may provide novel ideas for the treatment of TC.

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Cancer metabolism and intervention therapy

Molecular Biomedicine ◽

10.1186/s43556-020-00012-1 ◽

2021 ◽

Vol 2 (1) ◽

Author(s):

Huakan Zhao ◽

Yongsheng Li

Keyword(s):

Cancer Cells ◽

Tumor Cells ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Acid Synthesis ◽

Pentose Phosphate ◽

Metabolic Reprogramming ◽

Cancer Therapies ◽

Proliferation And Metastasis ◽

Immunosuppressive Microenvironment

AbstractMetabolic reprogramming with heterogeneity is a hallmark of cancer and is at the basis of malignant behaviors. It supports the proliferation and metastasis of tumor cells according to the low nutrition and hypoxic microenvironment. Tumor cells frantically grab energy sources (such as glucose, fatty acids, and glutamine) from different pathways to produce a variety of biomass to meet their material needs via enhanced synthetic pathways, including aerobic glycolysis, glutaminolysis, fatty acid synthesis (FAS), and pentose phosphate pathway (PPP). To survive from stress conditions (e.g., metastasis, irradiation, or chemotherapy), tumor cells have to reprogram their metabolism from biomass production towards the generation of abundant adenosine triphosphate (ATP) and antioxidants. In addition, cancer cells remodel the microenvironment through metabolites, promoting an immunosuppressive microenvironment. Herein, we discuss how the metabolism is reprogrammed in cancer cells and how the tumor microenvironment is educated via the metabolic products. We also highlight potential metabolic targets for cancer therapies.

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Phytochemicals Block Glucose Utilization and Lipid Synthesis to Counteract Metabolic Reprogramming in Cancer Cells

Applied Sciences ◽

10.3390/app11031259 ◽

2021 ◽

Vol 11 (3) ◽

pp. 1259

Author(s):

Qiong Wu ◽

Bo Zhao ◽

Guangchao Sui ◽

Jinming Shi

Keyword(s):

Cancer Cells ◽

Metabolic Pathways ◽

De Novo ◽

Aerobic Glycolysis ◽

Structural Characteristics ◽

Natural Compounds ◽

Metabolic Reprogramming ◽

De Novo Lipogenesis ◽

Anticancer Activities ◽

Substrate Analogs

Aberrant metabolism is one of the hallmarks of cancers. The contributions of dysregulated metabolism to cancer development, such as tumor cell survival, metastasis and drug resistance, have been extensively characterized. “Reprogrammed” metabolic pathways in cancer cells are mainly represented by excessive glucose consumption and hyperactive de novo lipogenesis. Natural compounds with anticancer activities are constantly being demonstrated to target metabolic processes, such as glucose transport, aerobic glycolysis, fatty acid synthesis and desaturation. However, their molecular targets and underlying anticancer mechanisms remain largely unclear or controversial. Mounting evidence indicated that these natural compounds could modulate the expression of key regulatory enzymes in various metabolic pathways at transcriptional and translational levels. Meanwhile, natural compounds could also inhibit the activities of these enzymes by acting as substrate analogs or altering their protein conformations. The actions of natural compounds in the crosstalk between metabolism modulation and cancer cell destiny have become increasingly attractive. In this review, we summarize the activities of natural small molecules in inhibiting key enzymes of metabolic pathways. We illustrate the structural characteristics of these compounds at the molecular level as either inhibitor of various enzymes or regulators of metabolic pathways in cancer cells. Our ultimate goal is to both facilitate the clinical application of natural compounds in cancer therapies and promote the development of novel anticancer therapeutics.

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Metabolic Remodeling Induced by Adipocytes: A New Achilles' Heel in Invasive Breast Cancer?

Current Medicinal Chemistry ◽

10.2174/0929867325666180426165001 ◽

2020 ◽

Vol 27 (24) ◽

pp. 3984-4001 ◽

Cited By ~ 4

Author(s):

Camille Attané ◽

Delphine Milhas ◽

Andrew J. Hoy ◽

Catherine Muller

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Cancer Cells ◽

Tumor Cells ◽

Fatty Acid Oxidation ◽

De Novo ◽

Metabolic Reprogramming ◽

Acid Oxidation ◽

Oxidation Inhibitors ◽

Metabolic Remodeling

Metabolic reprogramming represents an important hallmark of cancer cells. Besides de novo fatty acid synthesis, it is now clear that cancer cells can acquire Fatty Acids (FA) from tumor-surrounding adipocytes to increase their invasive capacities. Indeed, adipocytes release FA in response to tumor secreted factors that are transferred to tumor cells to be either stored as triglycerides and other complex lipids or oxidized in mitochondria. Like all cells, FA can be released over time from triglyceride stores through lipolysis and then oxidized in mitochondria in cancer cells. This metabolic interaction results in specific metabolic remodeling in cancer cells, and underpins adipocyte stimulated tumor progression. Lipolysis and fatty acid oxidation therefore represent novel targets of interest in the treatment of cancer. In this review, we summarize the recent advances in our understanding of the metabolic reprogramming induced by adipocytes, with a focus on breast cancer. Then, we recapitulate recent reports studying the effect of lipolysis and fatty acid oxidation inhibitors on tumor cells and discuss the interest to target these metabolic pathways as new therapeutic approaches for cancer.

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Resveratrol’s Anti-Cancer Effects through the Modulation of Tumor Glucose Metabolism

Cancers ◽

10.3390/cancers13020188 ◽

2021 ◽

Vol 13 (2) ◽

pp. 188

Author(s):

Aranka Brockmueller ◽

Saba Sameri ◽

Alena Liskova ◽

Kevin Zhai ◽

Elizabeth Varghese ◽

...

Keyword(s):

Glucose Metabolism ◽

Cancer Cells ◽

Tumor Cells ◽

Therapeutic Potential ◽

Current Knowledge ◽

Aerobic Glycolysis ◽

Energy Restriction ◽

Metabolic Reprogramming ◽

Cellular Targets ◽

Traditional Medicines

Tumor cells develop several metabolic reprogramming strategies, such as increased glucose uptake and utilization via aerobic glycolysis and fermentation of glucose to lactate; these lead to a low pH environment in which the cancer cells thrive and evade apoptosis. These characteristics of tumor cells are known as the Warburg effect. Adaptive metabolic alterations in cancer cells can be attributed to mutations in key metabolic enzymes and transcription factors. The features of the Warburg phenotype may serve as promising markers for the early detection and treatment of tumors. Besides, the glycolytic process of tumors is reversible and could represent a therapeutic target. So-called mono-target therapies are often unsafe and ineffective, and have a high prevalence of recurrence. Their success is hindered by the ability of tumor cells to simultaneously develop multiple chemoresistance pathways. Therefore, agents that modify several cellular targets, such as energy restriction to target tumor cells specifically, have therapeutic potential. Resveratrol, a natural active polyphenol found in grapes and red wine and used in many traditional medicines, is known for its ability to target multiple components of signaling pathways in tumors, leading to the suppression of cell proliferation, activation of apoptosis, and regression in tumor growth. Here, we describe current knowledge on the various mechanisms by which resveratrol modulates glucose metabolism, its potential as an imitator of caloric restriction, and its therapeutic capacity in tumors.

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The Role of Dyslipidemia in Colitis-Associated Colorectal Cancer

Journal of Oncology ◽

10.1155/2021/6640384 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Ke Chen ◽

Jianrong Guo ◽

Tao Zhang ◽

Jian Gu ◽

Huili Li ◽

...

Keyword(s):

Colorectal Cancer ◽

Epithelial Cells ◽

Tumor Cells ◽

Intestinal Inflammation ◽

Aerobic Glycolysis ◽

Lipid Synthesis ◽

Mucosal Damage ◽

Aberrant Crypt Foci ◽

Metabolic Reprogramming ◽

Lipid Lowering

Dyslipidemia, characterized by metabolic abnormalities, has become an important participant in colorectal cancer (CRC). Dyslipidemia aggravates intestinal inflammation, destroys the protective mucous layer, and disrupts the balance between injury and recovery. On the other hand, antioxidants induced by oxidative stress enhance glycolysis to maintain the acquisition of ATP allowing epithelial cells with damaged genomes to survive. In the repetitive phase of colitis, survival factors enable these epithelial cells to continuously proliferate. The main purpose is to restore and rebuild damaged mucosa, mainly aiming to recover mucosal damage and reconstruct mucosa, but it is also implicated in the occurrence and malignancy of CRC. The metabolic reprogramming of aerobic glycolysis and lipid synthesis enables these transformed epithelial cells to convert raw carbohydrate and amino acid substrates, thereby synthesizing protein and phospholipid biomass. Stearoyl-CoA desaturase, responsible for the fatty acid desaturation, improves the fluidity and permeability of cell membranes, which is one of the key factors affecting metabolic rate. In response to available fat, tumor cells reprogram their metabolism to better plunder energy-rich lipids and rapidly scavenge these lipids through continuous proliferation. However, lipid metabolic disorders inhibit the function of immune-infiltrating cells in the tumor microenvironment through the cross-talk between tumor cells and immunosuppressive stromal cells, thereby providing opportunities for tumor progress. Nonsteroidal anti-inflammatory drugs and lipid-lowering drugs can decrease the formation of aberrant crypt foci, lower the burden of the adenomatous polyp, and reduce the incidence of CRC. This review provides a comprehensive understanding of dyslipidemia on tumorigenesis and tumor progression and a development prospect of lipid disorders on tumor immunity.

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Elevated Expression of DecR1 Impairs ErbB2/Neu-Induced Mammary Tumor Development

Molecular and Cellular Biology ◽

10.1128/mcb.00686-07 ◽

2007 ◽

Vol 27 (18) ◽

pp. 6361-6371 ◽

Cited By ~ 30

Author(s):

Josie Ursini-Siegel ◽

Ashish B. Rajput ◽

Huiling Lu ◽

Virginie Sanguin-Gendreau ◽

Dongmei Zuo ◽

...

Keyword(s):

Breast Cancer ◽

Fatty Acid ◽

Cancer Cells ◽

Tumor Cells ◽

Mammary Tumor ◽

Fatty Acid Synthesis ◽

Breast Cancer Cells ◽

De Novo ◽

Acid Synthesis ◽

Mammary Tumor Cells

ABSTRACT Tumor cells utilize glucose as a primary energy source and require ongoing lipid biosynthesis for growth. Expression of DecR1, an auxiliary enzyme in the fatty acid β-oxidation pathway, is significantly diminished in numerous spontaneous mammary tumor models and in primary human breast cancer. Moreover, ectopic expression of DecR1 in ErbB2/Neu-induced mammary tumor cells is sufficient to reduce levels of ErbB2/Neu expression and impair mammary tumor outgrowth. This correlates with a decreased proliferative index and reduced rates of de novo fatty acid synthesis in DecR1-expressing breast cancer cells. Although DecR1 expression does not affect glucose uptake in ErbB2/Neu-transformed cells, sustained expression of DecR1 protects mammary tumor cells from apoptotic cell death following glucose withdrawal. Moreover, expression of catalytically impaired DecR1 mutants in Neu-transformed breast cancer cells restored Neu expression levels and increased mammary tumorigenesis in vivo. These results argue that DecR1 is sufficient to limit breast cancer cell proliferation through its ability to limit the extent of oncogene expression and reduce steady-state levels of de novo fatty acid synthesis. Furthermore, DecR1-mediated suppression of tumorigenesis can be uncoupled from its effects on Neu expression. Thus, while downregulation of Neu expression may contribute to DecR1-mediated tumor suppression in certain cell types, this is not an obligate event in all Neu-transformed breast cancer cells.

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Kinetic Analysis of Lipid Metabolism in Live Breast Cancer Cells via Nonlinear Optical Microscopy

10.1101/827931 ◽

2019 ◽

Author(s):

J. Hou ◽

N. E. Reid ◽

B. J. Tromberg ◽

E. O. Potma

Keyword(s):

Breast Cancer ◽

Lipid Metabolism ◽

Optical Microscopy ◽

Cancer Cells ◽

Breast Cancer Cells ◽

De Novo ◽

Lipid Synthesis ◽

Acid Synthesis ◽

Live Cells ◽

Consumption Rates

AbstractInvestigating the behavior of breast cancer cells via reaction kinetics may help unravel the mechanisms that underlie metabolic changes in tumors. However, obtaining human in vivo kinetic data is challenging due to difficulties associated with measuring these parameters. Non-destructive methods of measuring lipid content in live cells, provide a novel approach to quantitatively model lipid synthesis and consumption. In this study, two-photon excited fluorescence (TPEF) was used to determine metabolic rates via the cell’s optical redox ratio (ORR) as reported by fluorescence intensity ratios of metabolic coenzymes, nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FAD+). Concurrently, coherent Raman scattering (CRS) microscopy was used to probe de novo intracellular lipid content. Combining non-linear optical microscopy and Michaelis-Menten-kinetics based simulations, we isolated fatty acid synthesis/consumption rates and elucidated effects of altered lipid metabolism in T47D breast cancer cells. When treated with 17β-Estradiol (E2), cancer cells showed a 3-fold increase in beta-oxidation rate as well as a 50% increase in cell proliferation rate. Similarly, the rate of de novo lipid synthesis in cancer cells treated with E2 was increased by 60%. Furthermore, we treated T47D cells with etomoxir (ETO) and observed that cancer cells treated with ETO exhibited a ∼70% reduction in β-oxidation. These results show the ability to probe lipid alterations in live cells with minimum interruption, to characterize both glucose and lipid metabolism in breast cancer cells via quantitative kinetic models and parameters.Statement of SignificanceCombining non-linear optical microscopy (NLOM) and deuterium labeling provides insight into lipid metabolism in live cancer cells during cancer development and progression. The dynamic metabolic data is modelled with Michaelis-Menten-kinetics to independently quantify the lipid synthesis and utilization in cancer cells. Changes in lipid levels are found to originate from de novo lipid synthesis using glucose as a source, lipid consumption from β-oxidation and lipid consumption from cell proliferation, processes that can separately analyzed with the Michaelis-Menten model. In this work, we isolate fatty acid synthesis/consumption rates and elucidated effects of altered lipid metabolism in T47D breast cancer cells in response to estradiol stimulation and etomoxir treatment, dynamic processes that cannot be easily observed without the application of appropriate models.

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Untangling the Metabolic Reprogramming in Brain Cancer: Discovering Key Molecular Players Using Mass Spectrometry

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190729154543 ◽

2019 ◽

Vol 19 (17) ◽

pp. 1521-1534 ◽

Cited By ~ 6

Author(s):

Anatoly Sorokin ◽

Vsevolod Shurkhay ◽

Stanislav Pekov ◽

Evgeny Zhvansky ◽

Daniil Ivanov ◽

...

Keyword(s):

Mass Spectrometry ◽

Brain Cancer ◽

De Novo ◽

Aerobic Glycolysis ◽

Lipid Production ◽

Dietary Fatty Acids ◽

Metabolic Reprogramming ◽

Detection Methods ◽

Malignant Cells ◽

Proliferating Cells

Cells metabolism alteration is the new hallmark of cancer, as well as an important method for carcinogenesis investigation. It is well known that the malignant cells switch to aerobic glycolysis pathway occurring also in healthy proliferating cells. Recently, it was shown that in malignant cells de novo synthesis of the intracellular fatty acid replaces dietary fatty acids which change the lipid composition of cancer cells noticeably. These alterations in energy metabolism and structural lipid production explain the high proliferation rate of malignant tissues. However, metabolic reprogramming affects not only lipid metabolism but many of the metabolic pathways in the cell. 2-hydroxyglutarate was considered as cancer cell biomarker and its presence is associated with oxidative stress influencing the mitochondria functions. Among the variety of metabolite detection methods, mass spectrometry stands out as the most effective method for simultaneous identification and quantification of the metabolites. As the metabolic reprogramming is tightly connected with epigenetics and signaling modifications, the evaluation of metabolite alterations in cells is a promising approach to investigate the carcinogenesis which is necessary for improving current diagnostic capabilities and therapeutic capabilities. In this paper, we overview recent studies on metabolic alteration and oncometabolites, especially concerning brain cancer and mass spectrometry approaches which are now in use for the investigation of the metabolic pathway.

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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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Spot 14: A Marker of Aggressive Breast Cancer and a Potential Therapeutic Target

Endocrinology ◽

10.1210/en.2006-0463 ◽

2006 ◽

Vol 147 (9) ◽

pp. 4048-4055 ◽

Cited By ~ 31

Author(s):

William B. Kinlaw ◽

Jennifer L. Quinn ◽

Wendy A. Wells ◽

Christopher Roser-Jones ◽

Joel T. Moncur

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Therapeutic Target ◽

Milk Fat ◽

Breast Cancer Cells ◽

De Novo ◽

Lipid Synthesis ◽

Breast Cancers ◽

Spot 14 ◽

Aggressive Breast Cancer

Spot 14 (S14) is a nuclear protein that communicates the status of dietary fuels and fuel-related hormones to genes required for long-chain fatty acid synthesis. In mammary gland, S14 is important for both epithelial proliferation and milk fat production. The S14 gene is amplified in some breast cancers and is strongly expressed in most. High expression of S14 in primary invasive breast cancer is conspicuously predictive of recurrence. S14 mediates the induction of lipogenesis by progestin in breast cancer cells and accelerates their growth. Conversely, S14 knockdown impairs de novo lipid synthesis and causes apoptosis. We found that breast cancer cells do not express lipoprotein lipase (LPL) and hypothesize that they do not have access to circulating lipids unless the local environment supplies it. This may explain why primary breast cancers with low S14 do not survive transit from the LPL-rich mammary fat pad to areas devoid of LPL, such as lymph nodes, and thus do not appear as distant metastases. Thus, S14 is a marker for aggressive breast cancer and a potential target as well. Future effort will center on validation of S14 as a therapeutic target and producing antagonists of its action.

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