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

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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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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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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Phytometabolites Targeting the Warburg Effect in Cancer Cells: A Mechanistic Review

Current Drug Targets ◽

10.2174/1389450117666160401124842 ◽

2017 ◽

Vol 18 (9) ◽

Cited By ~ 21

Author(s):

Mohadeseh Hasanpourghadi ◽

Chung Yeng Looi ◽

Ashok Kumar Pandurangan ◽

Gautam Sethi ◽

Won Fen Wong ◽

...

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

The Warburg Effect

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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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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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A Genetically Encoded FRET Lactate Sensor and Its Use To Detect the Warburg Effect in Single Cancer Cells

PLoS ONE ◽

10.1371/journal.pone.0057712 ◽

2013 ◽

Vol 8 (2) ◽

pp. e57712 ◽

Cited By ~ 158

Author(s):

Alejandro San Martín ◽

Sebastián Ceballo ◽

Iván Ruminot ◽

Rodrigo Lerchundi ◽

Wolf B. Frommer ◽

...

Keyword(s):

Cancer Cells ◽

Warburg Effect ◽

Single Cancer ◽

Lactate Sensor ◽

The Warburg Effect

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Nitric oxide is a positive regulator of the Warburg effect in ovarian cancer cells

Cell Death and Disease ◽

10.1038/cddis.2014.264 ◽

2014 ◽

Vol 5 (6) ◽

pp. e1302-e1302 ◽

Cited By ~ 36

Author(s):

C A Caneba ◽

L Yang ◽

J Baddour ◽

R Curtis ◽

J Win ◽

...

Keyword(s):

Nitric Oxide ◽

Ovarian Cancer ◽

Cancer Cells ◽

Warburg Effect ◽

Ovarian Cancer Cells ◽

Positive Regulator ◽

The Warburg Effect

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LncRNA IDH1-AS1 links the functions of c-Myc and HIF1α via IDH1 to regulate the Warburg effect

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1711257115 ◽

2018 ◽

Vol 115 (7) ◽

pp. E1465-E1474 ◽

Cited By ~ 35

Author(s):

Shaoxun Xiang ◽

Hao Gu ◽

Lei Jin ◽

Rick F. Thorne ◽

Xu Dong Zhang ◽

...

Keyword(s):

Cell Proliferation ◽

Enzymatic Activity ◽

Cancer Cells ◽

Long Noncoding Rna ◽

Warburg Effect ◽

Noncoding Rna ◽

Ros Production ◽

Xenograft Growth ◽

The Relationship ◽

The Warburg Effect

The oncoprotein c-Myc plays an important role in regulating glycolysis under normoxia; yet, in cancer cells, HIF1α, which is essential for driving glycolysis under hypoxia, is often up-regulated even in the presence of oxygen. The relationship between these two major regulators of the Warburg effect remains to be fully defined. Here we demonstrate that regulation of a long noncoding RNA (lncRNA), named IDH1-AS1, enables c-Myc to collaborate with HIF1α in activating the Warburg effect under normoxia. c-Myc transcriptionally repressed IDH1-AS1, which, upon expression, promoted homodimerization of IDH1 and thus enhanced its enzymatic activity. This resulted in increased α-KG and decreased ROS production and subsequent HIF1α down-regulation, leading to attenuation of glycolysis. Hence, c-Myc repression of IDH1-AS1 promotes activation of the Warburg effect by HIF1α. As such, IDH1-AS1 overexpression inhibited cell proliferation, whereas silencing of IDH1-AS1 promoted cell proliferation and cancer xenograft growth. Restoring IDH1-AS1 expression may therefore represent a potential metabolic approach for cancer treatment.

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