Methionine Dependence of Cancer

Tumorigenesis is accompanied by the reprogramming of cellular metabolism. The shift from oxidative phosphorylation to predominantly glycolytic pathways to support rapid growth is well known and is often referred to as the Warburg effect. However, other metabolic changes and acquired needs that distinguish cancer cells from normal cells have also been discovered. The dependence of cancer cells on exogenous methionine is one of them and is known as methionine dependence or the Hoffman effect. This phenomenon describes the inability of cancer cells to proliferate when methionine is replaced with its metabolic precursor, homocysteine, while proliferation of non-tumor cells is unaffected by these conditions. Surprisingly, cancer cells can readily synthesize methionine from homocysteine, so their dependency on exogenous methionine reflects a general need for altered metabolic flux through pathways linked to methionine. In this review, an overview of the field will be provided and recent discoveries will be discussed.

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Hepatitis C Virus Downregulates Core Subunits of Oxidative Phosphorylation, Reminiscent of the Warburg Effect in Cancer Cells

Cells ◽

10.3390/cells8111410 ◽

2019 ◽

Vol 8 (11) ◽

pp. 1410 ◽

Cited By ~ 7

Author(s):

Gerresheim ◽

Roeb ◽

Michel ◽

Niepmann

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Citric Acid ◽

Oxidative Phosphorylation ◽

Cancer Cells ◽

Warburg Effect ◽

Citric Acid Cycle ◽

Host Cells ◽

Acid Cycle ◽

The Warburg Effect

Hepatitis C Virus (HCV) mainly infects liver hepatocytes and replicates its single-stranded plus strand RNA genome exclusively in the cytoplasm. Viral proteins and RNA interfere with the host cell immune response, allowing the virus to continue replication. Therefore, in about 70% of cases, the viral infection cannot be cleared by the immune system, but a chronic infection is established, often resulting in liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Induction of cancer in the host cells can be regarded to provide further advantages for ongoing virus replication. One adaptation in cancer cells is the enhancement of cellular carbohydrate flux in glycolysis with a reduction of the activity of the citric acid cycle and aerobic oxidative phosphorylation. To this end, HCV downregulates the expression of mitochondrial oxidative phosphorylation complex core subunits quite early after infection. This so-called aerobic glycolysis is known as the “Warburg Effect” and serves to provide more anabolic metabolites upstream of the citric acid cycle, such as amino acids, pentoses and NADPH for cancer cell growth. In addition, HCV deregulates signaling pathways like those of TNF-β and MAPK by direct and indirect mechanisms, which can lead to fibrosis and HCC.

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The Warburg effect: 80 years on

Biochemical Society Transactions ◽

10.1042/bst20160094 ◽

2016 ◽

Vol 44 (5) ◽

pp. 1499-1505 ◽

Cited By ~ 155

Author(s):

Michelle Potter ◽

Emma Newport ◽

Karl J. Morten

Keyword(s):

Cancer Cells ◽

High Glucose ◽

Warburg Effect ◽

Energy Requirement ◽

Glucose Consumption ◽

High Energy ◽

Metabolic Reprogramming ◽

Normal Cells ◽

Cancer Types ◽

The Warburg Effect

Influential research by Warburg and Cori in the 1920s ignited interest in how cancer cells' energy generation is different from that of normal cells. They observed high glucose consumption and large amounts of lactate excretion from cancer cells compared with normal cells, which oxidised glucose using mitochondria. It was therefore assumed that cancer cells were generating energy using glycolysis rather than mitochondrial oxidative phosphorylation, and that the mitochondria were dysfunctional. Advances in research techniques since then have shown the mitochondria in cancer cells to be functional across a range of tumour types. However, different tumour populations have different bioenergetic alterations in order to meet their high energy requirement; the Warburg effect is not consistent across all cancer types. This review will discuss the metabolic reprogramming of cancer, possible explanations for the high glucose consumption in cancer cells observed by Warburg, and suggest key experimental practices we should consider when studying the metabolism of cancer.

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Emerging Glycolysis Targeting and Drug Discovery from Chinese Medicine in Cancer Therapy

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2012/873175 ◽

2012 ◽

Vol 2012 ◽

pp. 1-13 ◽

Cited By ~ 8

Author(s):

Zhiyu Wang ◽

Neng Wang ◽

Jianping Chen ◽

Jiangang Shen

Keyword(s):

Drug Discovery ◽

Chinese Medicine ◽

Herbal Medicine ◽

Cancer Treatment ◽

Cancer Cells ◽

Warburg Effect ◽

Glycolytic Pathway ◽

Normal Cells ◽

Active Compounds ◽

The Warburg Effect

Molecular-targeted therapy has been developed for cancer chemoprevention and treatment. Cancer cells have different metabolic properties from normal cells. Normal cells mostly rely upon the process of mitochondrial oxidative phosphorylation to produce energy whereas cancer cells have developed an altered metabolism that allows them to sustain higher proliferation rates. Cancer cells could predominantly produce energy by glycolysis even in the presence of oxygen. This alternative metabolic characteristic is known as the “Warburg Effect.” Although the exact mechanisms underlying the Warburg effect are unclear, recent progress indicates that glycolytic pathway of cancer cells could be a critical target for drug discovery. With a long history in cancer treatment, traditional Chinese medicine (TCM) is recognized as a valuable source for seeking bioactive anticancer compounds. A great progress has been made to identify active compounds from herbal medicine targeting on glycolysis for cancer treatment. Herein, we provide an overall picture of the current understanding of the molecular targets in the cancer glycolytic pathway and reviewed active compounds from Chinese herbal medicine with the potentials to inhibit the metabolic targets for cancer treatment. Combination of TCM with conventional therapies will provide an attractive strategy for improving clinical outcome in cancer treatment.

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Metabolic Alterations in Cancer and Their Potential as Therapeutic Targets

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_175561 ◽

2017 ◽

pp. 825-832

Author(s):

Jamie D. Weyandt ◽

Craig B. Thompson ◽

Amato J. Giaccia ◽

W. Kimryn Rathmell

Keyword(s):

Tumor Growth ◽

Cancer Cells ◽

Tumor Cells ◽

Patient Outcomes ◽

Metabolic Changes ◽

Tumor Proliferation ◽

Therapeutic Targeting ◽

Normal Cells ◽

Metabolic Alterations ◽

Improve Patient

Otto Warburg’s discovery in the 1920s that tumor cells took up more glucose and produced more lactate than normal cells provided the first clues that cancer cells reprogrammed their metabolism. For many years, however, it was unclear as to whether these metabolic alterations were a consequence of tumor growth or an adaptation that provided a survival advantage to these cells. In more recent years, interest in the metabolic differences in cancer cells has surged, as tumor proliferation and survival have been shown to be dependent upon these metabolic changes. In this educational review, we discuss some of the mechanisms that tumor cells use for reprogramming their metabolism to provide the energy and nutrients that they need for quick or sustained proliferation and discuss the potential for therapeutic targeting of these pathways to improve patient outcomes.

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Thermodynamic Modeling of the Competition Between Cancer and Normal Cells

Journal of Non-Equilibrium Thermodynamics ◽

10.1515/jnet-2019-0037 ◽

2020 ◽

Vol 45 (1) ◽

pp. 19-25

Author(s):

Mostafa Sadeghi Ghuchani

Keyword(s):

Cancer Cells ◽

Entropy Production ◽

Production Rate ◽

Thermodynamic Model ◽

Warburg Effect ◽

Entropy Production Rate ◽

Metabolic Efficiency ◽

Normal Cells ◽

Functional Explanations ◽

The Warburg Effect

AbstractOne of the recognized differences between normal and cancer cells is in their metabolic profile. Tumor cells tend to produce energy through glycolysis rather than the much more efficient oxidative phosphorylation pathway, which healthy cells generally prefer. This phenomenon is identified as the Warburg effect. Although several functional explanations have been proposed for the Warburg effect, the competitive advantage of it is still subject of debate. Here we present a thermodynamic model to simulate the competition of cancer and normal cells in terms of bioenergetics. Our model shows that the Warburg effect has an advantage because the entropy production rate is increased and metabolic efficiency is decreased for cancer cells. Although inefficiency is generally considered a competitive disadvantage for living organisms, the thermodynamic model shows that it is not always the case. Indeed, when the energy resources are abundant and the system has a limited ability to export entropy, the organism with a higher rate of entropy production will have a higher chance of survival despite its lower metabolic efficiency. This thermodynamic model predicts that as long as there are enough nutrients in circulating blood, there are two thermodynamic strategies to control cancer cell populations, i. e., (i) decreasing the entropy production rate of cancer cells and (ii) increasing normal cells’ entropy production rate.

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Extracellular citrate and metabolic adaptations of cancer cells

Cancer and Metastasis Reviews ◽

10.1007/s10555-021-10007-1 ◽

2021 ◽

Author(s):

E. Kenneth Parkinson ◽

Jerzy Adamski ◽

Grit Zahn ◽

Andreas Gaumann ◽

Fabian Flores-Borja ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Cancer Cells ◽

Immune Cells ◽

Warburg Effect ◽

Cancer Metabolism ◽

Krebs Cycle ◽

Therapy Resistance ◽

Tumour Microenvironment ◽

The Warburg Effect

Abstract It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity.

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Macrosphelide A Exhibits a Specific Anti-Cancer Effect by Simultaneously Inactivating ENO1, ALDOA, and FH

Pharmaceuticals ◽

10.3390/ph14101060 ◽

2021 ◽

Vol 14 (10) ◽

pp. 1060

Author(s):

Kyoung Song ◽

Nirmal Rajasekaran ◽

Chaithanya Chelakkot ◽

Hunseok Lee ◽

Seungmann Paek ◽

...

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Fumarate Hydratase ◽

Metabolic Adaptation ◽

Normal Cells ◽

Target Proteins ◽

Anti Cancer ◽

The Warburg Effect

Aerobic glycolysis in cancer cells, also known as the Warburg effect, is an indispensable hallmark of cancer. This metabolic adaptation of cancer cells makes them remarkably different from normal cells; thus, inhibiting aerobic glycolysis is an attractive strategy to specifically target tumor cells while sparing normal cells. Macrosphelide A (MSPA), an organic small molecule, is a potential lead compound for the design of anti-cancer drugs. However, its role in modulating cancer metabolism remains poorly understood. MSPA target proteins were screened using mass spectrometry proteomics combined with affinity chromatography. Direct and specific interactions of MSPA with its candidate target proteins were confirmed by in vitro binding assays, competition assays, and simulation modeling. The siRNA-based knockdown of MSPA target proteins indirectly confirmed the cytotoxic effect of MSPA in HepG2 and MCF-7 cancer cells. In addition, we showed that MSPA treatment in the HEPG2 cell line significantly reduced glucose consumption and lactate release. MSPA also inhibited cancer cell proliferation and induced apoptosis by inhibiting critical enzymes involved in the Warburg effect: aldolase A (ALDOA), enolase 1 (ENO1), and fumarate hydratase (FH). Among these enzymes, the purified ENO1 inhibitory potency of MSPA was further confirmed to demonstrate the direct inhibition of enzyme activity to exclude indirect/secondary factors. In summary, MSPA exhibits anti-cancer effects by simultaneously targeting ENO1, ALDOA, and FH.

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Inhibition of mitochondrial pyruvate dehydrogenase kinase: a proposed mechanism by which melatonin causes cancer cells to overcome cytosolic glycolysis, reduce tumor biomass and reverse insensitivity to chemotherapy

Melatonin Research ◽

10.32794/mr11250033 ◽

2019 ◽

Vol 2 (3) ◽

pp. 105-119 ◽

Cited By ~ 19

Author(s):

Russel J Reiter ◽

Ramaswamy Sharma ◽

Qiang Ma ◽

Sergio Rosales-Corral ◽

Dario Acuna-Castroviejo ◽

...

Keyword(s):

Breast Cancer ◽

Oxidative Phosphorylation ◽

Cancer Cells ◽

Pyruvate Dehydrogenase ◽

Warburg Effect ◽

Breast Cancer Cells ◽

Pyruvate Dehydrogenase Kinase ◽

Cell Phenotype ◽

Acetyl Coa ◽

The Warburg Effect

This review presents a hypothesis to explain the role of melatonin in regulating glucose metabolism in cancer cells. Many cancer cells use cytosolic glycolysis (the Warburg effect) to produce energy (ATP). Under these conditions, glucose is primarily converted to lactate which is released into the blood in large quantities. The Warburg effect gives cancer cells advantages in terms of enhanced macromolecule synthesis required for accelerated cellular proliferation, reduced cellular apoptosis which enhances tumor biomass and a greater likelihood of metastasis. Based on available data, high circulating melatonin levels at night serve as a signal for breast cancer cells to switch from cytosolic glycolysis to mitochondrial glucose oxidation and oxidative phosphorylation for ATP production. In this situation, melatonin promotes the synthesis of acetyl-CoA from pyruvate; we speculate that melatonin does this by inhibiting the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) which normally inhibits pyruvate dehydrogenase complex (PDC), the enzyme that controls the pyruvate to acetyl-CoA conversion. Acetyl-CoA has several important functions in the mitochondria; it feeds into the citric acid cycle which improves oxidative phosphorylation and, additionally, it is a necessary co-factor for the rate limiting enzyme, arylalkylamine N-acetyltransferase, in mitochondrial melatonin synthesis. When breast cancer cells are using cytosolic glycolysis (during the day) they are of the cancer phenotype; at night when they are using mitochondria to produce ATP via oxidative phosphorylation, they have a normal cell phenotype. If this day:night difference in tumor cell metabolism is common in other cancers, it indicates that these tumor cells are only cancerous part of the time. We also speculate that high nighttime melatonin levels also reverse the insensitivity of tumors to chemotherapy.

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LncRNA OIP5-AS1 Regulates the Warburg Effect Through miR-124-5p/IDH2/HIF-1α Pathway in Cervical Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.655018 ◽

2021 ◽

Vol 9 ◽

Author(s):

Li Li ◽

Yan Ma ◽

Kamalibaike Maerkeya ◽

Davuti Reyanguly ◽

Lili Han

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Tumor Cells ◽

Warburg Effect ◽

Hypoxia Inducible Factor ◽

Hypoxic Condition ◽

Cervical Cancer Cells ◽

The Warburg Effect

Hypoxia reprogrammed glucose metabolism affects the Warburg effect of tumor cells, but the mechanism is still unclear. Long-chain non-coding RNA (lncRNA) has been found by many studies to be involved in the Warburg effect of tumor cells under hypoxic condition. Herein, we find that lncRNA OIP5-AS1 is up-regulated in cervical cancer tissues and predicts poor 5-years overall survival in cervical cancer patients, and it promotes cell proliferation of cervical cancer cells in vitro and in vivo. Moreover, OIP5-AS1 is a hypoxia-responsive lncRNA and is essential for hypoxia-enhanced glycolysis which is IDH2 or hypoxia inducible factor-1α (HIF-1α) dependent. In cervical cancer cells, OIP5-AS1 promotes IDH2 expression by inhibiting miR-124-5p, and IDH2 promotes the Warburg effect of cervical under hypoxic condition through regulating HIF-1α expression. In conclusion, hypoxia induced OIP5-AS1 promotes the Warburg effect through miR-124-5p/IDH2/HIF-1α pathway in cervical cancer.

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