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

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1410 ◽  
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.

scholarly journals Extracellular citrate and metabolic adaptations of cancer cells

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.

scholarly journals The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier

Biomolecules ◽  
2020 ◽  
Vol 10 (7) ◽  
pp. 1068 ◽  
Author(s):  
Joséphine Zangari ◽  
Francesco Petrelli ◽  
Benoît Maillot ◽  
Jean-Claude Martinou
Keyword(s):  
Citric Acid ◽  
Oxidative Phosphorylation ◽  
Neurodegenerative Diseases ◽  
Metabolic Disorders ◽  
Citric Acid Cycle ◽  
Cell Metabolism ◽  
Pyruvate Metabolism ◽  
Acid Cycle ◽  
Mitochondrial Pyruvate Carrier

Pyruvate, the end product of glycolysis, plays a major role in cell metabolism. Produced in the cytosol, it is oxidized in the mitochondria where it fuels the citric acid cycle and boosts oxidative phosphorylation. Its sole entry point into mitochondria is through the recently identified mitochondrial pyruvate carrier (MPC). In this review, we report the latest findings on the physiology of the MPC and we discuss how a dysfunctional MPC can lead to diverse pathologies, including neurodegenerative diseases, metabolic disorders, and cancer.

scholarly journals Targeting the Warburg effect in cancer cells through ENO1 knockdown rescues oxidative phosphorylation and induces growth arrest

Oncotarget ◽  
2015 ◽  
Vol 7 (5) ◽  
pp. 5598-5612 ◽  
Author(s):  
Michela Capello ◽  
Sammy Ferri-Borgogno ◽  
Chiara Riganti ◽  
Michelle Samuel Chattaragada ◽  
Moitza Principe ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Warburg Effect ◽  
Growth Arrest ◽  
The Warburg Effect

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

2019 ◽  
Vol 2 (3) ◽  
pp. 105-119 ◽  
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.

scholarly journals Methionine Dependence of Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 568 ◽  
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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