Decoding Warburg's hypothesis: tumor-related mutations in the mitochondrial respiratory chain

García-Heredia, José Manuel; Carnero, Amancio

doi:10.18632/oncotarget.6057

Cited by 43 publications

(43 citation statements)

References 133 publications

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“…In particular, the hypoglycemic-hyperglycemic transition promotes IGF-1 expression ( 29 , 30 ), and AKT is located downstream of IGF-1 in this pathway ( 31 ). Moreover, HIF-1α is a key factor necessary for switching the energy production pathway from OXPHOS to GL/LF through the activation of pyruvate dehydrogenase ( 32 , 33 ). This switching induces higher levels of side population, and promotes the expression of Nanog and Oct3/4 ( 34 ), which in turn activates stat3, resulting in the induction of Snail and a subsequent EMT phenotype ( 35 , 36 ).…”

Section: Discussionmentioning

confidence: 99%

Intermittent calorie restriction enhances epithelial-mesenchymal transition through the alteration of energy metabolism in a mouse tumor model

et al. 2017

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The effect of intermittent calorie restriction (ICR) on cancer is controversial. In this study, we examined the effects of ICR and food content in syngeneic BALB/c mice injected with CT26 mouse colon cancer cells. Mice were subjected to 24-h fasting once a week for 4 weeks, and then provided with a control, high-calorie, or trans fatty acid-rich diet. While ICR resulted in increases in tumor weights, metastasis and in the number of cancer stem cells (CSCs) in the tumors or blood of mice fed the control and high-fat diets, it had no effect on body weight after 4 weeks. In particular, we detected increases in the numbers of CSCs in the tumor or blood on the day after starvation, when food overconsumption was detected. Conversely, continuous calorie restriction had no effect on tumor weight, metastasis, or the number of CSCs in tumors or blood. In the post-starvation period, energy metabolism in the tumor was altered from oxidative phosphorylation to glycolysis/lactate fermentation, with the acquisition of the epithelial-mesenchymal transition (EMT) phenotype. Hyperglycemia at the post-starvation period induced the expression of insulin-like growth factor-1, hypoxia-induced factor-1α and Nanog, as well as the phosphorylation of Stat3. Taken together, these findings suggest that ICR induces an increase in the number of CSCs and enhances EMT by promoting the Warburg/Crabtree effect following post-fasting food overconsumption.

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Section: Discussionmentioning

confidence: 99%

Intermittent calorie restriction enhances epithelial-mesenchymal transition through the alteration of energy metabolism in a mouse tumor model

et al. 2017

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“…Additionally, a very recent study in our group has shown that TG2 ablation leads to mitophagy impairments and, in order to survive, the cells lacking this enzyme display a higher rate of aerobic glycolysis [ 32 ]. This important metabolic change suggests a role for the enzyme in the regulation of the cellular metabolism from mitochondrial respiration to aerobic glycolysis, which is typically detected in transformed cancer cells [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

The transglutaminase type 2 and pyruvate kinase isoenzyme M2 interplay in autophagy regulation

et al. 2015

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Autophagy is a self-degradative physiological process by which the cell removes worn-out or damaged components. Constant at basal level it may become highly active in response to cellular stress. The type 2 transglutaminase (TG2), which accumulates under stressful cell conditions, plays an important role in the regulation of autophagy and cells lacking this enzyme display impaired autophagy/mitophagy and a consequent shift their metabolism to glycolysis. To further define the molecular partners of TG2 involved in these cellular processes, we analysed the TG2 interactome under normal and starved conditions discovering that TG2 interacts with various proteins belonging to different functional categories. Herein we show that TG2 interacts with pyruvate kinase M2 (PKM2), a rate limiting enzyme of glycolysis which is responsible for maintaining a glycolytic phenotype in malignant cells and displays non metabolic functions, including transcriptional co-activation and protein kinase activity. Interestingly, the ablation of PKM2 led to the decrease of intracellular TG2's transamidating activity paralleled by an increase of its tyrosine phosphorylation. Along with this, a significant decrease of ULK1 and Beclin1 was also recorded, thus suggesting a block in the upstream regulation of autophagosome formation. These data suggest that the PKM2/TG2 interplay plays an important role in the regulation of autophagy in particular under cellular stressful conditions such as those displayed by cancer cells.

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“…In recent years, the Warburg effect has been reexamined 19 , 20 . Although it is well accepted that cancer cells possess a series of oncogene-directed metabolic reprogramming, which results in aerobic lactate production (Warburg effect) 21 , 22 , it is also known that proliferating cells enhance glycolysis for rapid ATP production and macromolecular biosynthesis and subsequently produce lactate aerobically 23 , 24 . In the present study, the HaCaT cells were collected at proliferating stage, so the cells might be able to express such metabolic properties.…”

Section: Discussionmentioning

confidence: 99%

Real-time monitoring system for evaluating the acid-producing activity of oral squamous cell carcinoma cells at different environmental pH

Morishima

Washio

Kitamura

et al. 2017

Sci Rep

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This study aimed to establish a real-time monitoring system for evaluating the acid-producing activity of cells and the effects of microenvironmental pH on their metabolism. Oral squamous cell carcinoma (HSC-2, HSC-3) and normal (HaCaT) cells were used. Their acid-producing activity from glucose, glutamine, and glutamate was monitored at various pH values using a pH stat system. Their production of lactic acid and ammonia was also measured. The acid-producing activity was monitored successfully. Both the cancer and normal cells produced acids from glucose, glutamine, and glutamate. All of the cells decreased their acid-producing activity as the environmental pH fell, but in glucose-derived acid-producing activity the cancer cells were more acid-tolerant than HaCaT cells. In the cancer cells, the proportion of lactic acid among all acids produced from glucose at the acidic environment tended to be higher than that in HaCaT cells. All of the cells produced ammonia from glutamine, while only HaCaT cells produced ammonia from glutamate. We established a real-time monitoring system for evaluating the acid-producing activity of cells. Our results suggest that the cancer cells possess acid-tolerant glucose metabolism with a tendency of metabolic shift to lactic acid production at acidic pH and they metabolise glutamate without ammonia production.

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Decoding Warburg's hypothesis: tumor-related mutations in the mitochondrial respiratory chain

Cited by 43 publications

References 133 publications

Intermittent calorie restriction enhances epithelial-mesenchymal transition through the alteration of energy metabolism in a mouse tumor model

Intermittent calorie restriction enhances epithelial-mesenchymal transition through the alteration of energy metabolism in a mouse tumor model

The transglutaminase type 2 and pyruvate kinase isoenzyme M2 interplay in autophagy regulation

Real-time monitoring system for evaluating the acid-producing activity of oral squamous cell carcinoma cells at different environmental pH

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