You may make misunderstanding that cancer cells exclusively show aerobic glycolysis, also referred to as Waburg effect. However, accumulating evidence shows that cancer cells exhibit mitochondrial metabolism with glutamine metabolism. That is why  cancer cells are sensitive to mitochondrial complex inhibitors.

Glucose and glutamine are absolutely required for cell division that feed into multiple pathways required to support cell growth. In actively growing cells, most of the glucose is secreted as lactate; the synthesis of lactate generates ATP required to maintain intracellular bioenergetics. The remaining glucose enters TCA cycle where it is metabolized to citrate. Within mitochondria of rapidly growing cells, most of the glucose-derived citrate is exported to support the synthesis of fatty acids required for cell growth. High citrate efflux from the mitochondria “empties” the TCA cycle. Glutamine “refills” the TCA cycle by a process termed anapleurosis.

You may make misunderstanding that cancer cells exclusively show aerobic glycolysis, also referred to as Waburg effect. However, accumulating evidence shows that cancer cells exhibit mitochondrial metabolism with glutamine metabolism. That is why  cancer cells are sensitive to mitochondrial complex inhibitors.

Glucose and glutamine are absolutely required for cell division that feed into multiple pathways required to support cell growth. In actively growing cells, most of the glucose is secreted as lactate; the synthesis of lactate generates ATP required to maintain intracellular bioenergetics. The remaining glucose enters TCA cycle where it is metabolized to citrate. Within mitochondria of rapidly growing cells, most of the glucose-derived citrate is exported to support the synthesis of fatty acids required for cell growth. High citrate efflux from the mitochondria “empties” the TCA cycle. Glutamine “refills” the TCA cycle by a process termed anapleurosis.

Thanks a lot for your clarification Dr. Go J Yoshida....

I do aware with the facts about glutaminolysis feeds the mitochondria and replenish the vacuum created by Citrate efflux ( fatty acid synthesis). 

But can you justify in contrast to the plasma concentration of Glucose (5 - 7 mM)  and Glutamine (?).   

Reply to Dr. Prakasam Gopinath; I am sorry that I cannot tell the exact glutamine concentration in vivo. However, in vitro experiments we often give glutamine in the cultured medium at the concentration of 4-5mM, while glucose at 5-10mM.

Pyruvate derived from glucose can provide acetyl-CoA and oxaloacetate to initiate the TCA while glutamine can also replenish the TCA metabolites through the process of glutaminolysis, where glutamine is converted to glutamate by glutaminases (GLSs), which then enters the TCA cycle by conversion into alphaketoglutarate by the aminotransferases or glutamate dehydrogenase. This glutaminolysis is promoted by the pro-oncogenic molecule c-Myc and the increased intracellular concentration of glutamine leads to activation of mTORC1.

On the other hand, cysteine/ glutamate transporter xCT (X(c-) system, encoded by SLC7a11), is responsible for brain edema accompanied by glioblastoma multiform (GBM). Antiporter system x(c)(-) transports cystine into cells in exchange for glutamate at a ratio of 1:1. Cystine is reduced into cysteine in the cytoplasm, the rate-limiting precursor of glutathione (GSH), an important small molecule antioxidant. Surely, this xCT-GSH axis helps cancer cells survive and proliferate under hyper-oxidative conditions, but the tumor-associated stromal microenvironment is rich in glutamate at the much higher concentration than expected, leading to cytotoxic edema.

http://www.ncbi.nlm.nih.gov/pubmed/18469825

Warburg effect is actually link to hypoxia. when the core area of cancer cells not get proper blood supply to get their nutrition then they generate food by  glycolysis (anaerobic respiration) try to do a experiment to know your answer that whether warburg effect is a potential target or not. You treat one batch of cancer cell lines with tirapazamine and one batch with tyrosine kinase type inhibitor like sunitinib (Do all this in hypoxic chamber) then see the change. then notice that how many cell survived. Treat another batch with tirapazamine and sunitinib in combination and then see how many cell survived.  the survival rate in tirapazamine treated,  sunitinib treated cell, and survival rate in combination will give a clear picture to you. then you can suggest that warburg have some effect on immortality of cells or not. you need to play with these two drugs in different way by using different cell culture based model like spheroid model and other innovative in vitro models only then you get your answer.

Thanks a lot Dr. Go J Yoshida for your valuable inputs.

Ravi: Warburg effect is not the same thing as the metabolism of glucose in cancer cells by glycolysis due to hypoxia. In fact, cancer cells will metabolize glucose by glycolysis (without proceeding further through citric acid cycle and the electron transport chain) also in the presence of oxygen and even in highly oxygenated tissues.

It is current understanding that aerobic glycolysis is driven by oncogenic signaling and not by mitochondrial dysfunction, hypoxia or mutations in genes coding for metabolic enzymes. Consequently, aerobic glycolysis may be suppressed by targeting oncogenic signalling, e.g. Akt and c-Myc, whose activation has been shown to promote aerobic glycolysis (for example, Akt promotes localization of glucose transporter GLUT1 to the cell surface). Another approach to target the Warburg effect is the inhibition of glycolytic enzymes that showed some specificity for cancer cells, or at least quantitative differences between cancer and normal cells, such as hexokinase-2 (HK2) or M2 isoform of pyruvate kinase (PKM2). Inhibition of GLUT1 transporter has also been explored as the way to target Warburg effect. 

I completely agree with Roman, Warburg effect is not the same thing as the metabolism of glucose. Indeed, the hyperactivation of glycolysis (in the presence of oxygen or aerobic glycolysis) it is not the only metabolic change that occurs in cancer cells (and in normal highly proliferative cells). This implies a global metabolic change to maintain the homeostasis of the whole metabolism (i.e endogenous fatty acid synthesis). These changes are focused in providing the “building blocks” and the reduction power for the general structures of dividing cells (i.e DNA, membranes system (fatty acids), proteins, etc…). We must take into account that although glycolysis is lesser effective in producing ATP than oxidative phosphorylation, the rate limiting resource for a dividing cells it is not ATP, but reduction power and the new “building blocks”, this means anabolism.

In my opinion, cancer cells proliferate in a much faster rate than normal cells.So in the development of tumor, it may encounter hypoxia and malnutrition most of the time within human body. That is probably why tumor cells develop such an active aerobic glycolysis pathway to adapt to the relative anoxic environment. However, the mitochondiral metabolic pathway is also present in cancer cells and disruption of this pathway leads to cancer cell death. This is probably because mitochondiral metabolic pathway can provide some essential intermediates for synthesis and cell growth. There is too much aerobic glycosis cannot provide, except for energy.

This may be of interest: http://www.nature.com/nature/journal/v517/n7536/full/517563a.html#comments