Extracellular citrate and metabolic adaptations of cancer cells

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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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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What do cellular responses to acidity tell us about cancer?

Cancer and Metastasis Reviews ◽

10.1007/s10555-021-10005-3 ◽

2021 ◽

Author(s):

Wiktoria Blaszczak ◽

Pawel Swietach

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

Cellular Responses ◽

Tumour Microenvironment ◽

Mathematical Framework ◽

Cellular Adaptation ◽

Somatic Evolution ◽

Chemical Microenvironment ◽

Therapeutic Responses ◽

The Warburg Effect

AbstractThe notion that invasive cancer is a product of somatic evolution is a well-established theory that can be modelled mathematically and demonstrated empirically from therapeutic responses. Somatic evolution is by no means deterministic, and ample opportunities exist to steer its trajectory towards cancer cell extinction. One such strategy is to alter the chemical microenvironment shared between host and cancer cells in a way that no longer favours the latter. Ever since the first description of the Warburg effect, acidosis has been recognised as a key chemical signature of the tumour microenvironment. Recent findings have suggested that responses to acidosis, arising through a process of selection and adaptation, give cancer cells a competitive advantage over the host. A surge of research efforts has attempted to understand the basis of this advantage and seek ways of exploiting it therapeutically. Here, we review key findings and place these in the context of a mathematical framework. Looking ahead, we highlight areas relating to cellular adaptation, selection, and heterogeneity that merit more research efforts in order to close in on the goal of exploiting tumour acidity in future therapies.

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Cancer Cells’ Low Sensitivity to Oxalate

10.20944/preprints202003.0390.v1 ◽

2020 ◽

Author(s):

Qiuyun Liu ◽

Xiaoxia Li ◽

Tianlun Lei ◽

Yilin Zhang ◽

Man Tang ◽

...

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

Cell Metabolism ◽

Krebs Cycle ◽

Cellular Respiration ◽

Malignant Cells ◽

Model Cell ◽

Cancer Cell Metabolism ◽

Low Sensitivity ◽

The Warburg Effect

The Warburg effect refers to the phenomenon that cancer cells produce energy via glycolysis instead of cellular respiration. Glycolysis generated no net protons. The Warburg effect may be malignant cells’ built-in mechanism to antagonize the buildup of protons via Krebs cycle and other pathways with compromised cellular respiration. Data described in this study indicated that cancer cells were less sensitive to the presence of oxalate than non-cancer model cell lines 16HBE14o- and HaCaT. Malignant cells may resort on organic acids such as oxalate and their calcium salts to antagonize strong acids. This experiment sheds light on the role of Warburg effect in cancer cell metabolism and homeostasis.

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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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Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K

Molecular Biology Reports ◽

10.1007/s11033-015-3858-x ◽

2015 ◽

Vol 42 (4) ◽

pp. 841-851 ◽

Cited By ~ 192

Author(s):

Rupert Courtnay ◽

Darleen C. Ngo ◽

Neha Malik ◽

Katherine Ververis ◽

Stephanie M. Tortorella ◽

...

Keyword(s):

Warburg Effect ◽

Cancer Metabolism ◽

The Warburg Effect

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Regulation of Cancer Metabolism by Deubiquitinating Enzymes: The Warburg Effect

International Journal of Molecular Sciences ◽

10.3390/ijms22126173 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6173

Author(s):

So-Hee Kim ◽

Kwang-Hyun Baek

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

Cancer Metabolism ◽

Ubiquitin Proteasome System ◽

Deubiquitinating Enzymes ◽

E3 Ligases ◽

Glycolysis Pathway ◽

Ubiquitin Proteasome ◽

Cell Growth And Proliferation ◽

The Warburg Effect

Cancer is a disorder of cell growth and proliferation, characterized by different metabolic pathways within normal cells. The Warburg effect is a major metabolic process in cancer cells that affects the cellular responses, such as proliferation and apoptosis. Various signaling factors down/upregulate factors of the glycolysis pathway in cancer cells, and these signaling factors are ubiquitinated/deubiquitinated via the ubiquitin–proteasome system (UPS). Depending on the target protein, DUBs act as both an oncoprotein and a tumor suppressor. Since the degradation of tumor suppressors and stabilization of oncoproteins by either negative regulation by E3 ligases or positive regulation of DUBs, respectively, promote tumorigenesis, it is necessary to suppress these DUBs by applying appropriate inhibitors or small molecules. Therefore, we propose that the DUBs and their inhibitors related to the Warburg effect are potential anticancer targets.

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Metabolic Reprogramming, Questioning, and Implications for Cancer

Biology ◽

10.3390/biology10020129 ◽

2021 ◽

Vol 10 (2) ◽

pp. 129

Author(s):

Pierre Jacquet ◽

Angélique Stéphanou

Keyword(s):

Cancer Research ◽

Warburg Effect ◽

Cancer Metabolism ◽

Metabolic Reprogramming ◽

Metabolic Adaptation ◽

Clear Definition ◽

The Warburg Effect

The expression “metabolic reprogramming” has been encountered more and more in the literature since the mid-1990s. It seems to encompass several notions depending on the author, but the lack of a clear definition allows it to be used as a “catch-all” expression. Our first intention is to point out the inconsistencies in the use of the reprogramming terminology for cancer metabolism. The second is to address the over-focus of the role of mutations in metabolic adaptation. With the increased interest in metabolism and, more specifically, in the Warburg effect in cancer research, it seems appropriate to discuss this terminology and related concepts in detail.

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Targeting Metabolism in Cancer Cells and the Tumour Microenvironment for Cancer Therapy

Molecules ◽

10.3390/molecules25204831 ◽

2020 ◽

Vol 25 (20) ◽

pp. 4831

Author(s):

Jiaqi Li ◽

Jie Qing Eu ◽

Li Ren Kong ◽

Lingzhi Wang ◽

Yaw Chyn Lim ◽

...

Keyword(s):

Cancer Cells ◽

Immune Cells ◽

Therapeutic Strategy ◽

Treatment Resistance ◽

Tumour Microenvironment ◽

Therapeutic Strategies ◽

Metabolic Reprogramming ◽

Cancer Associated Fibroblasts ◽

Tumour Metabolism

Targeting altered tumour metabolism is an emerging therapeutic strategy for cancer treatment. The metabolic reprogramming that accompanies the development of malignancy creates targetable differences between cancer cells and normal cells, which may be exploited for therapy. There is also emerging evidence regarding the role of stromal components, creating an intricate metabolic network consisting of cancer cells, cancer-associated fibroblasts, endothelial cells, immune cells, and cancer stem cells. This metabolic rewiring and crosstalk with the tumour microenvironment play a key role in cell proliferation, metastasis, and the development of treatment resistance. In this review, we will discuss therapeutic opportunities, which arise from dysregulated metabolism and metabolic crosstalk, highlighting strategies that may aid in the precision targeting of altered tumour metabolism with a focus on combinatorial therapeutic strategies.

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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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Methionine Dependence of Cancer

Biomolecules ◽

10.3390/biom10040568 ◽

2020 ◽

Vol 10 (4) ◽

pp. 568 ◽

Cited By ~ 6

Author(s):

Peter Kaiser

Keyword(s):

Oxidative Phosphorylation ◽

Cancer Cells ◽

Tumor Cells ◽

Rapid Growth ◽

Warburg Effect ◽

Metabolic Flux ◽

Metabolic Changes ◽

Normal Cells ◽

Methionine Dependence ◽

The Warburg Effect

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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