Carcinogenesis 38:119–133 PubMed Google Scholar. (, Potolicchio -. Cancer. (, Yeung . D. et al. (, Sonveaux . R.D. Therefore, aerobic exercise could contribute to counteract the metabolic switch to glycolytic metabolism in cancer cells and create epigenetic responses that could help in the restoration of oxidative phenotypes. In contrast to HIF-1 and c-Myc, the tumor and glycolytic pathway suppressor p53 is repressed in cancer (44–46). To reiterate from our Introduction, there is a renaissance of interest in the Warburg Effect in cancer research. et al. R.C. J. Further, it seems that in oxidative cancer cells, there is a reciprocal relationship between glutamate and lactate, as lactate promotes glutamate uptake and catabolism by increasing the expression of glutamine transporter ASCT2 and of glutaminase 1 (GLS1) (187). Reexamining How Cancer Cells Exploit the Body's Metabolic Resources. . A high glycolytic activity cannot be sustained without a matching and increased glucose uptake. C.M. et al. . And, as already noted, HIF-1 and c-Myc increase expression of glycolytic enzymes including LDHA (Figure 2). Carcinogenesis is the resultant of a complex orchestrated chain of genetic and metabolic events in which lactate production and accumulation play critical roles. et al. . The stress of accelerated lactate production in cancer cells is mitigated by overexpression of lactate transporters, symporters for lactate anions and protons that export lactic acid into the host. It is well documented that aerobic exercise increases mitochondrial function and lactate clearance capacity as well as increases fat oxidation and decreases glycolysis (32,34–37), thus decreasing reliance on glycogen and glucose, an anti-Warburg Effect affect. Such treatment is pH neutral or has, if anything, slightly alkalinizing effect (26). Action of GPR81 is mediated through c-AMP and CREB signaling pathways. Lactate increases extracellular acidosis of tumor microenvironment decreasing capacity of T-cell to export lactate, thus decreasing T-cell activity. To resolve these seemingly divergent findings additional studies need to be done to identify the roles of lactate in exosome participation in carcinogenesis. And finally, in this review we emphasize the effects of lactate anion from those of pH. Y. eif4f links translation to energy stress response in cancer. M. . (, Lauritzen A low pH increases exosomes release as well as uptake from recipient cells (196). K.H. et al. . (, Warburg (, Pérez-Escuredo CD147 (basigin), a plasma membrane glycoprotein that facilitates cellular surface expression of MCT1 and -4, has also been identified in exosomes derived from ovarian cancer cells (200). (, Oxford University Press is a department of the University of Oxford. In fact, during exercise, ~75–80% of the lactate produced in the muscle is oxidized to pyruvate for ATP synthesis in mitochondria of working muscles as well as in distant highly oxidative organs like the heart (139). M. The Warburg effect: essential part of metabolic reprogramming and central contributor to cancer progression. (, Fischer P. Subsequently, Warburg described that lactate was the end of glycolysis in cancer, but he did not delve into the meaning of lactate production and accumulation in cancer (2,101). et al. (, Hussien Warburg’s work lead to the hypothesis that cancer was a disease of abnormal cell metabolism, and although some researchers support the idea that mitochondrial malfunction is the beginning of cancer (11), there is contemporary consensus that mutations leading to metabolic dysregulation are first steps in progression to carcinogenesis (12). Through an orchestrated oncogene activation, tumor suppressor mutations and epigenetics, cancer cells in glycolytic tumors undergo a metabolic reprogramming transforming themselves into highly glycolytic and poorly oxidative cells with lactate formation as the end product despite normoxic conditions (12,38–40). . These reprogrammed activities are now recognized as hallmarks of cancer, and recent work has uncovered remarkable flexibility in the specific pathways activated by tumor cells to support these key functions. 2021 Mar 25;13(7):1518. doi: 10.3390/cancers13071518. B. I. San-Millán and G. A. Brooks, “Reexamining cancer metabolism: Lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect,” Carcinogenesis, vol. (, Draoui The tumor microenvironment consists of malignant cells, immune cells, non-cancer cell stromas, fibroblasts as well as the vasculature and lymphatics of the tumor. Because of the stimulus from training, well trained endurance athletes have the most developed mitochondrial capacity characterized by an increased lactate clearance and oxidation of any humans (147,148). Rather, in cancer, MCTs allow lactate to continue its journey outside the cell fulfilling its role as a mediator of carcinogenesis, which is a key concept we propose herein. W.C. Carcinogenesis. Am. The Emperor of All Maladies: A Biography of Cancer, Cerebral metabolism following traumatic brain injury: new discoveries with implications for treatment, Lactate: glycolytic end product and oxidative substrate during sustained exercise in mammals — the “lactate shuttle.”, Gilles, R. 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San-Millan I & Brooks GA 2017 Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect. et al. A. San-Millán I, Brooks GA. Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect. New generations of MCT-1 inhibitors like SR13800 and ACD3965 (currently in Phase 1/2 in the UK) have shown promising results in Raji cells (124) and small cell lung cancer (213) respectively. The development of MCT1 and MCT4’s inhibitors has enormous potential as an approach in cancer treatment as shown in different studies (22,126–128,166,209,210). A.J DOI: 10.1093/carcin/bgw127. Carcinogenesis. Biomembr., 39, 251–257. (, Bouzier Carcinogenesis. A Inactivation of PDH by HIF-1 is well known in exercise metabolism characterized by high glycolytic flux and lactate production (19), but in human exercise, lactate production is accompanied by well-regulated and rapid disposal via oxidation and gluconeogenesis under the Lactate Shuttle mechanism (19). et al. In glycolytic cancers, increased glycolysis is chronic which may deplete glycogen stores leading to increased proteolysis for gluconeogenesis, as well as for glutaminolysis to increase cytosolic pyruvate for lactate production. Carcinogenesis 38 119 – 133. et al. Lactate is directly involved in the ‘immune escape’ by decreasing monocyte migration and decreased activation of T cells as well as cytokine release and cytotoxic activity. 119–133, 2017. (, Medina Dichloroacetate and cancer: new home for an orphan drug? (, Dhup . . In our studies on normal and transformed cells, buffered media were used (21,23–25). Consequently, treatment with proton pump inhibitors results in a marked inhibition of exosomes release by tumor cells (197) and inhibition of exosomes uptake in melanoma cells (196). Furthermore, Draoui et al, showed that a new compound called 7-aminocarboxycoumarin (7ACC) inhibited lactate influx, but not efflux as well as cell proliferation in tumor cells expressing both MCT1 and MCT4 (127). Cancer stem cells are found in various cancer types and have been implicated in the resistance to therapeutic interventions in various cancers (204,205). L.A. V.R. Therefore, gluconeogenic mechanisms within precursors derived mainly from body corpus amino acid and protein reserves, ensure adequate glucose supply to cancer cells (Figure 1). (, Zhao Lactate has been subject of study for many decades and by important scientists including several Nobel Laureates. S Different approaches in interfering with lactate metabolism have already been successful in vitro and even in vivo (Figure 4). N. B.M. . Pereira-Nunes A, Afonso J, Granja S, Baltazar F. Adv Exp Med Biol. (, Arismendi-Morillo (, Le Floch 2017;38(2):119–33. (, Riethdorf (, Kankotia et al. Stroma surrounding cancer cells possess elevated levels of hyaluronan which increases cancer growth and motility of cancer cells (162,163). HIF-1 activates pyruvate dehydrogenase kinase-1 (PDK-1) that phosphorylates and inactivates PDH that limits oxidative disposal of pyruvate and, thereby favors diversion of the glycolytic flux to lactate. Article. As well, c-MYC cooperates with HIF-1 in activating several genes encoding for glycolytic proteins including LDHA. For full access to this pdf, sign in to an existing account, or purchase an annual subscription. Exposure to lactate by cells has been shown to rapidly increase both MCT1 mRNA and protein expression (21). . D.M. Traductions en contexte de "ERREURS INNEES DU METABOLISME" en français-anglais avec Reverso Context : PROCEDE EMPECHANT LE DEVELOPPEMENT D'UN DYSFONCTIONNEMENT METABOLIQUE GRAVE EN RAPPORT AVEC LES ERREURS INNEES DU METABOLISME (, Roth Thompson CB(1), Palm W(1). . 127 - 133 , 10.1093/carcin/bgw127 Google Scholar . 1A) ... the induction of excess nutrient metabolism in cancer cells has consequences beyond cell intrinsic effects. et al. The fact that oncogenes and tumor suppressor mutations directly increase the expression of MCTs shows that the highly orchestrated metabolic reprogramming in cancer cells to glycolysis and lactate production does not just stop at the end of the Warburg Effect. Therefore, it should be possible to alter some metabolic links and events necessary for lactagenesis and lactate shuttling and therefore carcinogenesis. et al. . a ‘lactormone’) with major regulatory properties. et al. C. (, Bonnet N. et al. u/dem0n0cracy. . Despite LDHA exhibiting carcinogenesis in various … As IDH mutations are likely to be involved in malignant transformation of chondrosarcomas, we aimed to … 4) A. Garrido and N. Djouder, “NAD + Deficits in Age-Related Diseases and Cancer”, Trends Cancer, 2017, 3(8), 593. It has been also known for about two decades that lactate level is highly correlated with metastasis in different forms of cancers (150,159,169–172). . et al. A novel … et al. However lack of MCT specificity has been a problem. eCollection 2021. (, Brooks After a hiatus of several decades, interest in lactate as a player in cancer has been renewed. . R. (, Ge Deleting CD147 gene with ‘zinc finger nucleases’ (ZFN’s) has also shown to decreases MCT1 and MCT4 expression and decrease lactate export in non-small cell lung cancer (222). Archived. Lactate plays a central role in the bioenergetics, self-sufficiency and sustainability of cancer cells. K. Weglarz-Tomczak E, Mondeel TDGA, Piebes DGE, Westerhoff HV. . . V. . 2021 Apr 3;11(12):5889-5910. doi: 10.7150/thno.56157. et al. The weakness of cancer resides in its complexity and the highly orchestrated processes that are rare events in nature. Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg effect. In our studies on … (, Polet D. (, Dubouchaud Carcinogenesis. . 7. Front Microbiol. Lactate can enter tumor endothelial cells and lactate released from tumor cells through MCT4 is enough to stimulate angiogenesis and tumor growth (161).
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