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

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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Proton export drives the Warburg Effect

10.1101/2021.09.20.461019 ◽

2021 ◽

Author(s):

Shonagh Russell ◽

Liping Xu ◽

Yoonseok Kam ◽

Dominique Abrahams ◽

Bryce Ordway ◽

...

Keyword(s):

Warburg Effect ◽

Cancer Metabolism ◽

Aerobic Glycolysis ◽

Lactate Production ◽

Glycolytic Enzymes ◽

Hek293 Cells ◽

Driver Mutations ◽

The Warburg Effect

Aggressive cancers commonly ferment glucose to lactic acid at high rates, even in the presence of oxygen. This is known as aerobic glycolysis, or the “Warburg Effect”. It is widely assumed that this is a consequence of the upregulation of glycolytic enzymes. Oncogenic drivers can increase the expression of most proteins in the glycolytic pathway, including the terminal step of exporting H+ equivalents from the cytoplasm. Proton exporters maintain an alkaline cytoplasmic pH, which can enhance all glycolytic enzyme activities, even in the absence of oncogene-related expression changes. Based on this observation, we hypothesized that increased uptake and fermentative metabolism of glucose could be driven by the expulsion of H+ equivalents from the cell. To test this hypothesis, we stably transfected lowly-glycolytic MCF-7, U2-OS, and glycolytic HEK293 cells to express proton exporting systems: either PMA1 (yeast H+-ATPase) or CAIX (carbonic anhydrase 9). The expression of either exporter in vitro enhanced aerobic glycolysis as measured by glucose consumption, lactate production, and extracellular acidification rate. This resulted in an increased intracellular pH, and metabolomic analyses indicated that this was associated with an increased flux of all glycolytic enzymes upstream of pyruvate kinase. These cells also demonstrated increased migratory and invasive phenotypes in vitro, and these were recapitulated in vivo by more aggressive behavior, whereby the acid-producing cells formed higher grade tumors with higher rates of metastases. Neutralizing tumor acidity with oral buffers reduced the metastatic burden. Therefore, cancer cells with increased H+ export increase intracellular alkalization, even without oncogenic driver mutations, and this is sufficient to alter cancer metabolism towards a Warburg phenotype.

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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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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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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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Everolimus regulates the activity of gemcitabine-resistant pancreatic cancer cells by targeting the Warburg effect via PI3K/AKT/mTOR signaling

Molecular Medicine ◽

10.1186/s10020-021-00300-8 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Jing Cui ◽

Yao Guo ◽

Heshui Wu ◽

Jiongxin Xiong ◽

Tao Peng

Keyword(s):

Pancreatic Cancer ◽

Glucose Metabolism ◽

Cell Viability ◽

Cancer Cells ◽

Warburg Effect ◽

Aerobic Glycolysis ◽

Mtor Signaling ◽

Glucose Transporter 1 ◽

Pancreatic Cancer Cells ◽

The Warburg Effect

Abstract Background Gemcitabine (GEM) resistance remains a significant clinical challenge in pancreatic cancer treatment. Here, we investigated the therapeutic utility of everolimus (Evr), an inhibitor of mammalian target of rapamycin (mTOR), in targeting the Warburg effect to overcome GEM resistance in pancreatic cancer. Methods The effect of Evr and/or mTOR overexpression or GEM on cell viability, migration, apoptosis, and glucose metabolism (Warburg effect) was evaluated in GEM-sensitive (GEMsen) and GEM-resistant (GEMres) pancreatic cancer cells. Results We demonstrated that the upregulation of mTOR enhanced cell viability and favored the Warburg effect in pancreatic cancer cells via the regulation of PI3K/AKT/mTOR signaling. However, this effect was counteracted by Evr, which inhibited aerobic glycolysis by reducing the levels of glucose, lactic acid, and adenosine triphosphate and suppressing the expression of glucose transporter 1, lactate dehydrogenase-B, hexokinase 2, and pyruvate kinase M2 in GEMsen and GEMres cells. Evr also promoted apoptosis by upregulating the pro-apoptotic proteins Bax and cytochrome-c and downregulating the anti-apoptotic protein Bcl-2. GEM was minimally effective in suppressing GEMres cell activity, but the therapeutic effectiveness of Evr against pancreatic cancer growth was greater in GEMres cells than that in GEMsen cells. In vivo studies confirmed that while GEM failed to inhibit the progression of GEMres tumors, Evr significantly decreased the volume of GEMres tumors while suppressing tumor cell proliferation and enhancing tumor apoptosis in the presence of GEM. Conclusions Evr treatment may be a promising strategy to target the growth and activity of GEM-resistant pancreatic cancer cells by regulating glucose metabolism via inactivation of PI3K/AKT/mTOR signaling.

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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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Inverse correlation between heme synthesis and the Warburg effect in cancer cells

10.1101/753079 ◽

2019 ◽

Cited By ~ 1

Author(s):

Yuta Sugiyama ◽

Erika Takahashi ◽

Kiwamu Takahashi ◽

Motowo Nakajima ◽

Tohru Tanaka ◽

...

Keyword(s):

Electron Transfer ◽

Cancer Cells ◽

Cancer Cell ◽

Warburg Effect ◽

Metabolic Adaptation ◽

Human Gastric Cancer ◽

Transfer System ◽

Heme Synthesis ◽

Electron Transfer System ◽

The Warburg Effect

AbstractsCancer cells show a bias toward the glycolytic system over the conventional mitochondrial electron transfer system for obtaining energy. This biased metabolic adaptation is called the Warburg effect. Cancer cells also exhibit a characteristic metabolism, a decreased heme synthesizing ability. Here we show that heme synthesis and the Warburg effect are inversely correlated. We used human gastric cancer cell lines to investigate glycolytic metabolism and electron transfer system toward promotion/inhibition of heme synthesis. Under hypoxic conditions, heme synthesis was suppressed and the glycolytic system was enhanced. Addition of a heme precursor for the promotion of heme synthesis led to an enhanced electron transfer system and inhibited the glycolytic system and vice versa. Enhanced heme synthesis leads to suppression of cancer cell proliferation by increasing intracellular reactive oxygen species levels. Collectively, the promotion of heme synthesis in cancer cells eliminated the Warburg effect by shifting energy metabolism from glycolysis to oxidative phosphorylation.

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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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Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy

Cancer Control ◽

10.1177/10732748211041243 ◽

2021 ◽

Vol 28 ◽

pp. 107327482110412

Author(s):

Karolina Kozal ◽

Paweł Jóźwiak ◽

Anna Krześlak

Keyword(s):

Glucose Metabolism ◽

Cancer Therapy ◽

Cancer Cells ◽

Warburg Effect ◽

Metabolic Reprogramming ◽

Metabolic Phenotype ◽

Metabolic Adaptation ◽

Drug Bioavailability ◽

Altered Glucose ◽

The Warburg Effect

In the 1920s, Otto Warburg observed the phenomenon of altered glucose metabolism in cancer cells. Although the initial hypothesis suggested that the alteration resulted from mitochondrial damage, multiple studies of the subject revealed a precise, multistage process rather than a random pattern. The phenomenon of aerobic glycolysis emerges not only from mitochondrial abnormalities common in cancer cells, but also results from metabolic reprogramming beneficial for their sustenance. The Warburg effect enables metabolic adaptation of cancer cells to grow and proliferate, simultaneously enabling their survival in hypoxic conditions. Altered glucose metabolism of cancer cells includes, inter alia, qualitative and quantitative changes within glucose transporters, enzymes of the glycolytic pathway, such as hexokinases and pyruvate kinase, hypoxia-inducible factor, monocarboxylate transporters, and lactate dehydrogenase. This review summarizes the current state of knowledge regarding inhibitors of cancer glucose metabolism with a focus on their clinical potential. The altered metabolic phenotype of cancer cells allows for targeting of specific mechanisms, which might improve conventional methods in anti-cancer therapy. However, several problems such as drug bioavailability, specificity, toxicity, the plasticity of cancer cells, and heterogeneity of cells in tumors have to be overcome when designing therapies based on compounds targeted in cancer cell energy metabolism.

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