scholarly journals Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism

2006 ◽  
Vol 175 (6) ◽  
pp. 913-923 ◽  
Author(s):  
Hélène Pelicano ◽  
Rui-hua Xu ◽  
Min Du ◽  
Li Feng ◽  
Ryohei Sasaki ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Mitochondrial Respiration ◽  
Warburg Effect ◽  
Survival Advantage ◽  
Mitochondrial Dna Deletion ◽  
Atp Production ◽  
Akt Activation ◽  
Survival Pathway ◽  
The Warburg Effect

Cancer cells exhibit increased glycolysis for ATP production due, in part, to respiration injury (the Warburg effect). Because ATP generation through glycolysis is less efficient than through mitochondrial respiration, how cancer cells with this metabolic disadvantage can survive the competition with other cells and eventually develop drug resistance is a long-standing paradox. We report that mitochondrial respiration defects lead to activation of the Akt survival pathway through a novel mechanism mediated by NADH. Respiration-deficient cells (ρ-) harboring mitochondrial DNA deletion exhibit dependency on glycolysis, increased NADH, and activation of Akt, leading to drug resistance and survival advantage in hypoxia. Similarly, chemical inhibition of mitochondrial respiration and hypoxia also activates Akt. The increase in NADH caused by respiratory deficiency inactivates PTEN through a redox modification mechanism, leading to Akt activation. These findings provide a novel mechanistic insight into the Warburg effect and explain how metabolic alteration in cancer cells may gain a survival advantage and withstand therapeutic agents.

How the Warburg effect supports aggressiveness and drug resistance of cancer cells?

2018 ◽  
Vol 38 ◽  
pp. 1-11 ◽  
Author(s):  
Philippe Icard ◽  
Seth Shulman ◽  
Diana Farhat ◽  
Jean-Marc Steyaert ◽  
Marco Alifano ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cancer Cells ◽  
Warburg Effect ◽  
The Warburg Effect

Non-dietary Fructose Metabolism Contributes to the Warburg effect in Cancers

2020 ◽  
Author(s):  
Bing Han ◽  
Lu Wang ◽  
Meilin Wei ◽  
Cynthia Rajani ◽  
Runming Wei ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
Glucose Transporter ◽  
Self Control ◽  
Metabolic Reprogramming ◽  
Atp Production ◽  
Fructose Metabolism ◽  
Energy Needs ◽  
Dietary Fructose ◽  
The Warburg Effect

AbstractFructose metabolism is increasingly recognized as a preferred energy source for cancer cell proliferation. However, dietary fructose rarely enters the bloodstream. Therefore, it remains unclear how cancer cells acquire a sufficient amount of fructose to supplement their energy needs. Here we report that the cancer cells can convert glucose into fructose through intra- and extracellular polyol pathways. The fructose metabolism bypasses normal aerobic respiration’s self-control to supply excessive metabolites to glycolysis and causes the Warburg effect. Inhibition of fructose production drastically suppressed glycolysis and ATP production in cancers. Furthermore, we determined that a glucose transporter, SLC2A8/GLUT8, exports intracellular fructose to other cells in the tumor microenvironment. Taken together, our study identified overlooked fructose resources for cancer cells as an essential part of their metabolic reprogramming and caused the Warburg effect.Statement of SignificanceOur findings in this study suggest that the Warburg effect is actually achieved by means of fructose metabolism, instead of glucose metabolism alone. Fructose metabolism results in accelerated glycolysis and an increased amount of ATP and key intermediates for anabolic metabolism.

scholarly journals Warburg Effect, Glutamine, Succinate, Alanine, When Oxygen Matters

Biology ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1000
Author(s):  
Frédéric Bouillaud ◽  
Noureddine Hammad ◽  
Laurent Schwartz
Keyword(s):  
Mitochondrial Respiration ◽  
Warburg Effect ◽  
Aerobic Glycolysis ◽  
Glucose Consumption ◽  
Glycolytic Flux ◽  
Atp Production ◽  
Lactate Release ◽  
General Metabolism ◽  
Cellular Bioenergetics ◽  
The Warburg Effect

Cellular bioenergetics requires an intense ATP turnover that is increased further by hypermetabolic states caused by cancer growth or inflammation. Both are associated with metabolic alterations and, notably, enhancement of the Warburg effect (also known as aerobic glycolysis) of poor efficiency with regard to glucose consumption when compared to mitochondrial respiration. Therefore, beside this efficiency issue, other properties of these two pathways should be considered to explain this paradox: (1) biosynthesis, for this only indirect effect should be considered, since lactate release competes with biosynthetic pathways in the use of glucose; (2) ATP production, although inefficient, glycolysis shows other advantages when compared to mitochondrial respiration and lactate release may therefore reflect that the glycolytic flux is higher than required to feed mitochondria with pyruvate and glycolytic NADH; (3) Oxygen supply becomes critical under hypermetabolic conditions, and the ATP/O2 ratio quantifies the efficiency of oxygen use to regenerate ATP, although aerobic metabolism remains intense the participation of anaerobic metabolisms (lactic fermentation or succinate generation) could greatly increase ATP/O2 ratio; (4) time and space constraints would explain that anaerobic metabolism is required while the general metabolism appears oxidative; and (5) active repression of respiration by glycolytic intermediates, which could ensure optimization of glucose and oxygen use.

scholarly journals Metabolic regulation of Akt: roles reversed

2006 ◽  
Vol 175 (6) ◽  
pp. 845-847 ◽  
Author(s):  
Jonathan L. Coloff ◽  
Jeffrey C. Rathmell
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
Metabolic Regulation ◽  
Tumor Biology ◽  
Metabolic Phenotype ◽  
Phosphatidylinositol 3 Kinase ◽  
Mitochondrial Mutation ◽  
Survival Pathway ◽  
Respiration Deficiency ◽  
The Warburg Effect

The respiration-deficient, highly glycolytic metabolic phenotype of cancer cells known as the “Warburg effect” has been appreciated for many years. A new study (see Pelicano et al. on p. 913 of this issue) demonstrates that respiration deficiency caused by mitochondrial mutation or hypoxia may directly promote the enormous survival advantage observed in cancer cells by activation of the phosphatidylinositol 3-kinase–Akt survival pathway. We discuss these and other recent findings that show how metabolic changes associated with cancer can play a significant role in tumor biology.

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

2017 ◽  
Vol 18 (9) ◽  
Author(s):  
Mohadeseh Hasanpourghadi ◽  
Chung Yeng Looi ◽  
Ashok Kumar Pandurangan ◽  
Gautam Sethi ◽  
Won Fen Wong ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
The Warburg Effect

Metabolic reprogramming for cancer cells and their microenvironment: Beyond the Warburg Effect

2018 ◽  
Vol 1870 (1) ◽  
pp. 51-66 ◽  
Author(s):  
Linchong Sun ◽  
Caixia Suo ◽  
Shi-ting Li ◽  
Huafeng Zhang ◽  
Ping Gao
Keyword(s):  
Cancer Cells ◽  
Warburg Effect ◽  
Metabolic Reprogramming ◽  
The Warburg Effect

scholarly journals Investigation of energy metabolic dynamism in hyperthermia-resistant ovarian and uterine cancer cells under heat stress

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Taisei Kanamori ◽  
Natumi Miyazaki ◽  
Shigeki Aoki ◽  
Kousei Ito ◽  
Akihiro Hisaka ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Uterine Cancer ◽  
Mitochondrial Oxidative Phosphorylation ◽  
Ubiquitin Pathway ◽  
Atp Production ◽  
Skov3 Cells ◽  
Pathway Analyses ◽  
Rate Limiting ◽  
Glycolytic Rate ◽  
The Warburg Effect

AbstractDespite progress in the use of hyperthermia in clinical practice, the thermosensitivity of cancer cells is poorly understood. In a previous study, we found that sensitivity to hyperthermia varied between ovarian and uterine cancer cell lines. Upon hyperthermia, glycolytic enzymes decreased in hyperthermia-resistant SKOV3 cells. However, the mechanisms of glycolysis inhibition and their relationship with thermoresistance remain to be explored. In this study, metabolomic analysis indicated the downregulation of glycolytic metabolites in SKOV3 cells after hyperthermia. Proteomic and pathway analyses predicted that the ubiquitin pathway was explicitly activated in resistant SKOV3 cells, compared with hyperthermia-sensitive A2780 cells, and STUB1, a ubiquitin ligase, potentially targeted PKM, a glycolytic rate-limiting enzyme. PKM is degraded via ubiquitination upon hyperthermia. Although glycolysis is inactivated by hyperthermia, ATP production is maintained. We observed that oxygen consumption and mitochondrial membrane potential were activated in SKOV3 cells but suppressed in A2780 cells. The activation of mitochondria could compensate for the loss of ATP production due to the suppression of glycolysis by hyperthermia. Although the physiological significance has not yet been elucidated, our results demonstrated that metabolomic adaptation from the Warburg effect to mitochondrial oxidative phosphorylation could contribute to thermoresistance in ovarian and uterine cancer cells.

scholarly journals Mitochondria Targeting as an Effective Strategy for Cancer Therapy

2020 ◽  
Vol 21 (9) ◽  
pp. 3363 ◽  
Author(s):  
Poorva Ghosh ◽  
Chantal Vidal ◽  
Sanchareeka Dey ◽  
Li Zhang
Keyword(s):  
Cancer Therapy ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Mitochondrial Respiration ◽  
Mitochondrial Dynamics ◽  
Metastatic Tumor ◽  
Atp Production ◽  
Development Of Resistance ◽  
Mitochondrial Alterations ◽  
Mitochondria Targeting

Mitochondria are well known for their role in ATP production and biosynthesis of macromolecules. Importantly, increasing experimental evidence points to the roles of mitochondrial bioenergetics, dynamics, and signaling in tumorigenesis. Recent studies have shown that many types of cancer cells, including metastatic tumor cells, therapy-resistant tumor cells, and cancer stem cells, are reliant on mitochondrial respiration, and upregulate oxidative phosphorylation (OXPHOS) activity to fuel tumorigenesis. Mitochondrial metabolism is crucial for tumor proliferation, tumor survival, and metastasis. Mitochondrial OXPHOS dependency of cancer has been shown to underlie the development of resistance to chemotherapy and radiotherapy. Furthermore, recent studies have demonstrated that elevated heme synthesis and uptake leads to intensified mitochondrial respiration and ATP generation, thereby promoting tumorigenic functions in non-small cell lung cancer (NSCLC) cells. Also, lowering heme uptake/synthesis inhibits mitochondrial OXPHOS and effectively reduces oxygen consumption, thereby inhibiting cancer cell proliferation, migration, and tumor growth in NSCLC. Besides metabolic changes, mitochondrial dynamics such as fission and fusion are also altered in cancer cells. These alterations render mitochondria a vulnerable target for cancer therapy. This review summarizes recent advances in the understanding of mitochondrial alterations in cancer cells that contribute to tumorigenesis and the development of drug resistance. It highlights novel approaches involving mitochondria targeting in cancer therapy.

scholarly journals Cell-Type Specific Metabolic Response of Cancer Cells to Curcumin

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.

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

PLoS ONE ◽  
2013 ◽  
Vol 8 (2) ◽  
pp. e57712 ◽  
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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