These results were validated by western blot (Figure ?(Figure2).2). the nature of this relation, the metabolism may represent a new target to avoid or to block the mechanism that has been impairing treatment success. In this mini-review, we discuss the relation between metabolism and MDR resistance focusing on the multiple non-metabolic functions that enzymes of the glycolytic pathway are known to display, with emphasis with the diverse activities of glyceraldehyde-3-phosphate dehydrogenase. TAK-441 gene expression and synthesis of functional proteins are induced by hypoxic environments (6). Furthermore, ABC transporters are expressed not only in MDR cancer cells, but also in a number of stem and progenitor cells. Additionally, it has been reported that TAK-441 hypoxia promotes an undifferentiated cell state in various stem and precursor cell populations, as well as in cancer stem cells (7C9). In this respect, it has also been suggested that NOTCH signaling is involved. However, it must be recalled that when cells are under hypoxic conditions, there is a metabolic shift from oxidative phosphorylation to glycolysis (10). This situation contrasts with cells under normoxia, in which glucose is first anaerobically catabolized to pyruvate which is then further catabolized along the Krebs cycle where NADH and FADH2 are reoxidized by the respiratory chain associated to the electron transport system. Incidentally, glycolysis is a hallmark in many types of tumor cells (11). This phenotype is in TAK-441 fact the basis of the so-called Warburg effect, also known as aerobic glycolysis. The Warburg effect describes a situation in which the glycolytic pathway is fully activated even in the presence of adequate oxygen supply (12). Although Warburg originally proposed that cancer was due to an impairment of mitochondrial function, it is accepted today that these organelles retain full oxidative capacities. It must be described, however, that apart from reddish blood cells, aerobic glycolysis is definitely common in highly proliferative cells, whether tumoral or not. Stem cells are a case in point (13). The common belief that cells undergoing glycolysis selected an inefficient form of energy production is definitely misguided. Barring the comparative stoichiometry of ATP formation between glycolysis and OXPHOS, aerobic glycolysis is in fact an efficient form of ATP production due to the kinetic properties of the enzymes participating in the pathway which afford very fast fluxes compatible with the ATP demand of the rapidly growing cells. Beyond its part in bioenergetics, glycolysis constitutes a branch of the pentose phosphate pathway (PPP), since glucose-6-phosphate is also the substrate for glucose-6-phosphate dehydrogenase, the 1st enzyme of that pathway. Therefore, glycolysis also contributes to the production of precursors for the biosynthesis of nucleotides (generation of ribulose-5-phosphate). In addition, the PPP pathway promotes the formation of NADPH, an essential coenzyme for reductive biosynthetic processes such as that of fatty acids. NADPH also has an important part in keeping the redox equilibrium. Similarly, glycolysis can be considered as an anaplerotic pathway by way of its participation in amino acids synthesis (3-phosphoglycerate or pyruvate). Therefore, from an energetic stand point glycolysis more than compensates the relatively small amounts of ATP produced when compared with oxidative phosphorylation. However, it must be emphasized that tumors are in fact constituted by a mosaic of different cellular subpopulations. As such, from your biochemical perspective tumors can also be envisaged as being functionally heterogeneous. Accordingly, within the context of types of rate of metabolism, tumors can be perceived as composed of subsets of resistant quiescent/slow-cycling cells that occasionally rely more on mitochondrial respiration and PCDH9 less on glycolysis. Similarly the same tumor could also harbor cells that are specifically glycolytic (14, 15). Interestingly, the possibility of a switch that regulates mitochondrial function in the case of TAK-441 metastasis has been proposed. The results of Porporato et al. showed that overburdening the electron transport system may be an essential step in enhancing migration of cells and (16). The authors concluded that in order to accomplish metastasis, mitochondria must be active, although not necessarily functional. By extension such findings suggest that in tumor cells there may be switches that constantly activate/inactivate mitochondrial function depending on changes dictated from the microenvironment that impact, for example, the availability of metabolites. The intermittent switching between anaerobic and oxidative rate of metabolism seems to be a feature of metastasis. Relating to this plan, accumulating data display that there is a tradeoff including growth versus migration, i.e., cells which are proliferating prevalently show a.
