Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation

Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These metabolic alterations include (1) a shift from oxidative phosphorylation to aerobic glycolysis to support the increased need for ATP, (2) increased glutaminolysis for NADPH regeneration, (3) altered flux through the pentose phosphate pathway and the tricarboxylic acid cycle for macromolecule generation, (4) increased lipid uptake, lipogenesis, and cholesterol synthesis, (5) upregulation of one-carbon metabolism for the production of ATP, NADH/NADPH, nucleotides, and glutathione, (6) altered amino acid metabolism, (7) metabolism-based regulation of apoptosis, and (8) the utilization of alternative substrates, such as lactate and acetate. Altered metabolic flux in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, and other regulatory molecules, including non-coding RNAs. Changes to metabolic pathways in cancer are dynamic, exhibit plasticity, and are often dependent on the type of tumor and the tumor microenvironment, leading in a shift of thought from the Warburg Effect and the “reverse Warburg Effect” to metabolic plasticity. Understanding the complex nature of altered flux through these multiple pathways in cancer cells can support the development of new therapies.

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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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HIF-1-Dependent Reprogramming of Glucose Metabolic Pathway of Cancer Cells and Its Therapeutic Significance

International Journal of Molecular Sciences ◽

10.3390/ijms20020238 ◽

2019 ◽

Vol 20 (2) ◽

pp. 238 ◽

Cited By ~ 69

Author(s):

Ayako Nagao ◽

Minoru Kobayashi ◽

Sho Koyasu ◽

Christalle C. T. Chow ◽

Hiroshi Harada

Keyword(s):

Cancer Cells ◽

Metabolic Pathway ◽

Warburg Effect ◽

Aerobic Glycolysis ◽

Hypoxia Inducible Factor ◽

Pentose Phosphate ◽

Adaptive Responses ◽

Acid Fermentation ◽

Hypoxia Inducible Factor 1 ◽

The Warburg Effect

Normal cells produce adenosine 5′-triphosphate (ATP) mainly through mitochondrial oxidative phosphorylation (OXPHOS) when oxygen is available. Most cancer cells, on the other hand, are known to produce energy predominantly through accelerated glycolysis, followed by lactic acid fermentation even under normoxic conditions. This metabolic phenomenon, known as aerobic glycolysis or the Warburg effect, is less efficient compared with OXPHOS, from the viewpoint of the amount of ATP produced from one molecule of glucose. However, it and its accompanying pathway, the pentose phosphate pathway (PPP), have been reported to provide advantages for cancer cells by producing various metabolites essential for proliferation, malignant progression, and chemo/radioresistance. Here, focusing on a master transcriptional regulator of adaptive responses to hypoxia, the hypoxia-inducible factor 1 (HIF-1), we review the accumulated knowledge on the molecular basis and functions of the Warburg effect and its accompanying pathways. In addition, we summarize our own findings revealing that a novel HIF-1-activating factor enhances the antioxidant capacity and resultant radioresistance of cancer cells though reprogramming of the glucose metabolic pathway.

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The POU2F1-ALDOA axis promotes the proliferation and chemoresistance of colon cancer cells by enhancing glycolysis and the pentose phosphate pathway activity

Oncogene ◽

10.1038/s41388-021-02148-y ◽

2022 ◽

Author(s):

Jinguan Lin ◽

Longzheng Xia ◽

Linda Oyang ◽

Jiaxin Liang ◽

Shiming Tan ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Cells ◽

Pentose Phosphate Pathway ◽

Aerobic Glycolysis ◽

Human Colon ◽

Pentose Phosphate ◽

Metabolic Reprogramming ◽

Colon Cancer Cells ◽

Human Colon Cancer ◽

Pou Domain

AbstractCancer metabolic reprogramming enhances its malignant behaviors and drug resistance, which is regulated by POU domain transcription factors. This study explored the effect of POU domain class 2 transcription factor 1 (POU2F1) on metabolic reprogramming in colon cancer. The POU2F1 expression was analyzed in GEO dataset, TCGA cohorts and human colon cancer tissues by bioinformatics and immunohistochemistry. The effects of altered POU2F1 expression on proliferation, glucose metabolism and oxaliplatin sensitivity of colon cancer cells were tested. The impacts of POU2F1 on aldolase A (ALDOA) expression and malignant behaviors of colon cancer cells were examined. We found that up-regulated POU2F1 expression was associated with worse prognosis and oxaliplatin resistance in colon cancer. POU2F1 enhanced the proliferation, aerobic glycolysis and the pentose phosphate pathway (PPP) activity, but reduced oxidative stress and apoptosis in colon cancer cells, dependent on up-regulating ALDOA expression. Mechanistically, POU2F1 directly bound to the ALDOA promoter to enhance the ALDOA promoter activity in colon cancer cells. Moreover, activation of the POU2F1-ALDOA axis decreased the sensitivity to oxaliplatin in colon cancer cells. These data indicate that the POU2F1-ALDOA axis promotes the progression and oxaliplatin resistance by enhancing metabolic reprogramming in colon cancer. Our findings suggest that the POU2F1-ALDOA axis may be new therapeutic targets to overcome oxaliplatin resistance in colon cancer.

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Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer ◽

10.1016/j.bbcan.2018.06.005 ◽

2018 ◽

Vol 1870 (1) ◽

pp. 51-66 ◽

Cited By ~ 44

Author(s):

Linchong Sun ◽

Caixia Suo ◽

Shi-ting Li ◽

Huafeng Zhang ◽

Ping Gao

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

Metabolic Reprogramming ◽

The Warburg Effect

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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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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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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 Key Role of the WNT/β-Catenin Pathway in Metabolic Reprogramming in Cancers under Normoxic Conditions

Cancers ◽

10.3390/cancers13215557 ◽

2021 ◽

Vol 13 (21) ◽

pp. 5557

Author(s):

Alexandre Vallée ◽

Yves Lecarpentier ◽

Jean-Noël Vallée

Keyword(s):

Tumor Microenvironment ◽

Tumor Growth ◽

Warburg Effect ◽

Target Genes ◽

Glucose Transporter ◽

Aerobic Glycolysis ◽

Lactate Production ◽

Metabolic Reprogramming ◽

Pyruvate Dehydrogenase Kinase ◽

The Warburg Effect

The canonical WNT/β-catenin pathway is upregulated in cancers and plays a major role in proliferation, invasion, apoptosis and angiogenesis. Nuclear β-catenin accumulation is associated with cancer. Hypoxic mechanisms lead to the activation of the hypoxia-inducible factor (HIF)-1α, promoting glycolytic and energetic metabolism and angiogenesis. However, HIF-1α is degraded by the HIF prolyl hydroxylase under normoxia, conditions under which the WNT/β-catenin pathway can activate HIF-1α. This review is therefore focused on the interaction between the upregulated WNT/β-catenin pathway and the metabolic processes underlying cancer mechanisms under normoxic conditions. The WNT pathway stimulates the PI3K/Akt pathway, the STAT3 pathway and the transduction of WNT/β-catenin target genes (such as c-Myc) to activate HIF-1α activity in a hypoxia-independent manner. In cancers, stimulation of the WNT/β-catenin pathway induces many glycolytic enzymes, which in turn induce metabolic reprogramming, known as the Warburg effect or aerobic glycolysis, leading to lactate overproduction. The activation of the Wnt/β-catenin pathway induces gene transactivation via WNT target genes, c-Myc and cyclin D1, or via HIF-1α. This in turn encodes aerobic glycolysis enzymes, including glucose transporter, hexokinase 2, pyruvate kinase M2, pyruvate dehydrogenase kinase 1 and lactate dehydrogenase-A, leading to lactate production. The increase in lactate production is associated with modifications to the tumor microenvironment and tumor growth under normoxic conditions. Moreover, increased lactate production is associated with overexpression of VEGF, a key inducer of angiogenesis. Thus, under normoxic conditions, overstimulation of the WNT/β-catenin pathway leads to modifications of the tumor microenvironment and activation of the Warburg effect, autophagy and glutaminolysis, which in turn participate in tumor growth.

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Metabolic Reprogramming of Chemoresistant Cancer Cells and the Potential Significance of Metabolic Regulation in the Reversal of Cancer Chemoresistance

Metabolites ◽

10.3390/metabo10070289 ◽

2020 ◽

Vol 10 (7) ◽

pp. 289 ◽

Cited By ~ 2

Author(s):

Xun Chen ◽

Shangwu Chen ◽

Dongsheng Yu

Keyword(s):

Drug Resistance ◽

Cancer Cells ◽

Tumor Cells ◽

Metabolic Regulation ◽

Metabolic Response ◽

Pentose Phosphate ◽

Metabolic Reprogramming ◽

Acid Oxidation ◽

Drug Resistant ◽

Chemotherapy Drugs

Metabolic reprogramming is one of the hallmarks of tumors. Alterations of cellular metabolism not only contribute to tumor development, but also mediate the resistance of tumor cells to antitumor drugs. The metabolic response of tumor cells to various chemotherapy drugs can be analyzed by metabolomics. Although cancer cells have experienced metabolic reprogramming, the metabolism of drug resistant cancer cells has been further modified. Metabolic adaptations of drug resistant cells to chemotherapeutics involve redox, lipid metabolism, bioenergetics, glycolysis, polyamine synthesis and so on. The proposed metabolic mechanisms of drug resistance include the increase of glucose and glutamine demand, active pathways of glutaminolysis and glycolysis, promotion of NADPH from the pentose phosphate pathway, adaptive mitochondrial reprogramming, activation of fatty acid oxidation, and up-regulation of ornithine decarboxylase for polyamine production. Several genes are associated with metabolic reprogramming and drug resistance. Intervening regulatory points described above or targeting key genes in several important metabolic pathways may restore cell sensitivity to chemotherapy. This paper reviews the metabolic changes of tumor cells during the development of chemoresistance and discusses the potential of reversing chemoresistance by metabolic regulation.

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Cell-Type Specific Metabolic Response of Cancer Cells to Curcumin

International Journal of Molecular Sciences ◽

10.3390/ijms21051661 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1661

Author(s):

Anamarija Mojzeš ◽

Marko Tomljanović ◽

Lidija Milković ◽

Renata Novak Kujundžić ◽

Ana Čipak Gašparović ◽

...

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Warburg Effect ◽

Aerobic Glycolysis ◽

Intracellular Localization ◽

Lactate Production ◽

Glucose Consumption ◽

Cell Type ◽

Cell Type Specific ◽

The Warburg Effect

In order to support uncontrolled proliferation, cancer cells need to adapt to increased energetic and biosynthetic requirements. One such adjustment is aerobic glycolysis or the Warburg effect. It is characterized by increased glucose uptake and lactate production. Curcumin, a natural compound, has been shown to interact with multiple molecules and signaling pathways in cancer cells, including those relevant for cell metabolism. The effect of curcumin and its solvent, ethanol, was explored on four different cancer cell lines, in which the Warburg effect varied. Vital cellular parameters (proliferation, viability) were measured along with the glucose consumption and lactate production. The transcripts of pyruvate kinase 1 and 2 (PKM1, PKM2), serine hydroxymethyltransferase 2 (SHMT2) and phosphoglycerate dehydrogenase (PHGDH) were quantified with RT-qPCR. The amount and intracellular localization of PKM1, PKM2 and signal transducer and activator of transcription 3 (STAT3) proteins were analyzed by Western blot. The response to ethanol and curcumin seemed to be cell-type specific, with respect to all parameters analyzed. High sensitivity to curcumin was present in the cell lines originating from head and neck squamous cell carcinomas: FaDu, Detroit 562 and, especially, Cal27. Very low sensitivity was observed in the colon adenocarcinoma-originating HT-29 cell line, which retained, after exposure to curcumin, a higher levels of lactate production despite decreased glucose consumption. The effects of ethanol were significant.

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