I believe that the answer to the question is not known. One hypothesis is that In the absence of glucose and the presence of oxygen, cells could switch to glutaminolysis. The TCA cycle is then being filled by glutamine. In this scenario, the cell would switch to aerobic glycolysis since the TCA cycle is being fed from glutaminolysis.

Hi Mikko. I think that the shift in the metabolism is an adaptation to hypoxic conditions during the early avascular phase of tumour development. In hypoxia situation the oxidative phosphorylation is impossible and this situation occur same latter, in vascularized tumors, since the tumor vascularization is not perfect. There are others possible explanations, like the point of view that glycolysis has the capacity to generate ATP at a higher rate than oxidative phosphorylation and so would be advantageous as long as glucose supplies are not limited. Sorry by the bad english.

Hi, I think initially proliferating cells have normal conditions to undergo aerobic glycolysis, but later on hypoxia in cells prevent cells to go to ETC cycle for ATP synthesis and therefore, pathway is changed to lactate production. Moreover, these cells start expressing pyruvate kinase M2 , a different enzyme that goes to lactic acid cycle instead of kreb cycle.

Hello Herman! I understand that under hypoxic conditions cells use anearobic glycolysis for ATP production. But why would cells do that under glucose/serum starvation under normoxic conditions? What do you mean by saying "glycolysis has the capacity to generate ATP at higher rate"? Do you mean that it is faster? Because certainly it is not more efficient net ATP yield from anaerobic glycolysis from one glucose molecule is something like 2ATP but from complete aerobic oxidative phosphorylation cycle around 36 ATP from one glucose molecule.

Hello Monika. I guess my question was a bit poorly presented because you also misunderstood it to some extent like Herman. Now, I edited the typo from the headline, by aerobic glycolysis I meant anaerobic.. =) Sorry.

Glucose deprivation induce a state called hypoxia, where insufficient oxygen, carbon dioxide ratio (O2:CO2) decreased enough to disrupt the TCA cycle i.e aerobic respiration. Meantime, the end product of glycolysis is pyruvate whose destiny will depend on the O2: CO2 level, if it is proper it will follow the aerobic oxiation pathway i.e. TCA cycle otherwise anaerobic pathway and get converted to lactate.

Now the question is proliferative cells/ cancer cells show this phenomenon:

Answer is simple:

1.Low level of glucose induce hypoxia which means either cell has to invade to the neighboring cells to hijack their nutrients and nourishing molecules or either it has to rapidly divide to decrease it energy requirements.

2.Cancer or highly proliferative cells need acidic medium to grow, which is provided by the lactate synthesis via. anaerobic respiration. This is the other reason of requirement of low level of glucose by proliferative cells.

Conclusion: Low level of glucose cause hypoxia which make better conditions for proliferating cells

Moikka! Good question that I don't think the research community has all the answsers to yet. Here are some good reviews related to cancer cells and metabolic effects which might help.

Nähdäan,

Elahu

Koppenol WH, Bounds PL & Dang CV 2011 Otto Warburg's contributions to current concepts of cancer metabolism. Nature reviews.Cancer 11 325-337. (doi:10.1038/nrc3038; 10.1038/nrc3038).

Hanahan D & Weinberg RA 2011 Hallmarks of cancer: the next generation. Cell 144 646-674. (doi:10.1016/j.cell.2011.02.013; 10.1016/j.cell.2011.02.013).

Vander Heiden MG, Cantley LC & Thompson CB 2009 Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science Signaling 324 1029.

I guess it makes sense that, under anaerobic conditions, a dividing cell switches to anaerobic glycolysis. Later, when those same cells find themselves under normoxic conditins they find that anaerobic glycolysis have several advantages for a fast growing cell and keep that as an evolutionary advantage:

It produces an excess of acid (lactate, mostly) that induces growth inhibition in non-tumour cells and the extracellular matrix to loosen (in other words, there is more room and food for the tumour cell).

Although it is paradoxycal, anaerobic glycolysis is "more effective" for a fast growing cell. Those cells do need energy but, more than that, they need building blocks to keep their proliferation. CO2 is no good for a cell that requires the synthesis of huge amounts of lipids, proteins and other complex molecules. It is best to leave the glucose half-burnt and use part of the pyruvate and lactate as building blocks.

These are, of course, working hypothesis under evaluation by people in the field of cancer and yeast metabolism (the latter also do anaerobic glycolysis under normoxic conditions when they want to grow fast). Of course, I do not claim I am right.

The tumor cells have damaged mitochondria (impaired OxPhos), so they rely on glycolysis and substrate level phosporylation to make ATP.

Impaired OxPhos causes compensatory fermentation via oncogen activation

I believe that the answer to the question is not known. One hypothesis is that In the absence of glucose and the presence of oxygen, cells could switch to glutaminolysis. The TCA cycle is then being filled by glutamine. In this scenario, the cell would switch to aerobic glycolysis since the TCA cycle is being fed from glutaminolysis.

Hi Mikko!!!. Very good question that it has been without any answer until a few years ago that metabolis has re-emerged. Otto Warbrug defined that in both scenarios (high glucose or low glucose) tumor cells use preferentially anarobic glycolisis (obtaining 2 ATP/mol of glucose) instead of oxidative phosphorylation (36 ATP/mol of glucose). The reason is for production of pyruvate the building block of the majority of macromolecules. Furthermore, anaerobic glycolysis is much more rapid that oxidative phosphorylation is. So, although is less efficient present other advantages for tumor cells. Good luck!!

I concur totally withDominic, damaged mitochondria in malignant cells are the culprit.

http://www.academia.edu/4254683/The_bio-energetic_theory_of_carcinogenesis

Mikko

I think that your concentration on the cellular level might be misleading? After all, cells are part of tissue, organ and the whole body. Glucose deprivation on a whole body level indue a conflict between the given tissue needs (say milk production, growth, etc) and an whole body need (say, enhanced immune demand under microbial attack). Thus, the cellular response you described may reflect a programed response, which is relevant on the whole organism metabolism scale as demonstrated i my recent in press publication in the Journal of Dairy Science:

Article: Early mammary gland metabolic and immune responses during natural-like and forceful drying-off in high-yielding dairy cows.

I'm not sure it is damaged mitochondria. Some cancer cells possess high aerobic glycolysis AND high mitochondrial activity, and the balance between the two may change during disease progression and WITHIN a single tumor. At least with respect to melanoma http://www.molecular-cancer.com/content/11/1/76

Mikko,

Sorry, I did not complete my former argument, as follow:

In time of whole body glucose shortage, 'the body" will shunt glucose utilization in non-essential tissue (in terms of existence; say mammary gland, ovary) to spare the glucose for tissues in which glucose is essential for the whole organism function (say, brain cells, cardiac and immune cells). Thus, it is predicted that glucose derivation of normal nerve, cardiac, or leukocytes will not induce a switch toward anaerobic glycolysis and lactate production

Elahu please check article by Thomas Seyfried "Cancer as a metabolic Disease".High mitochondrial activity does not equal Oxidative phosphorylation.

http://www.nutritionandmetabolism.com/content/pdf/1743-7075-7-7.pdf

I think a lot has been said on Mikko's question.

Agustin's answer very well described the advantages for rapidly proliferating cancer cells in enhancing the glycolytic flux over oxidative phosphorylation - that is, the need to produce biosynthetic precursors.

Yet, to address Mikko's question, one has to consider the rate of glucose consumption when it is metabolized by a) glycolysis and lactate dehydrogenase versus b) oxidative phosphorylation. In one of Warburg's papers in 1927, he observed that cancer tissues consumed on average ~7 times more glucose by aerobic glycolysis than normal tissues, which use oxidative phosphorylation (OXPHOS) and do not exhibit lactate secretion in normal circumstances. In the already mentioned review of Koppenol ( Koppenol WH, Bounds PL & Dang CV 2011 Otto Warburg's contributions to current concepts of cancer metabolism. Nature reviews.Cancer 11 325-337.), it is explained that Warburg's studies (using the reaction vessels with tissue slices) showed that, the time a normal cell takes to consume 1 glucose molecule through OXPHOS is the same the cancer cell takes to consume 13 glucose molecules, only one of which through OXPHOS. This means that the combined action of glycolysis and lactate dehydrogenase is faster than OXPHOS.

This leads me to the next part of the answer to Mikko's question, which has to do with the production rate or flux.

Carlos Guillen partially alluded to this by referring that " anaerobic glycolysis is much more rapid that oxidative phosphorylation is. So, although is less efficient present other advantages for tumor cells."

I would say that anaerobic glycolysis is not less efficient that oxidative phosphorylation. On the contrary, it is quite efficient and can provide as much ATP as OXPHOS in a cancer cell. One cannot only consider the ATP yield (the 31 versus 2 ATPs, it is not 36), but also the ATP production rate Please, see the following article on this: Science. 2001 Apr 20;292(5516):504-7.

Overall, I think there is a lot to Mikko's question. For example, one can also think of the GLUT1 expression levels and their coupling with high glycolysis. I think the bottom line is that the allosteric regulation and signaling pathways underlying metabolism can rewire cancer cells to rely on anerobic glycolysis upon a "glucose crisis", because indeed this is a situation where an efficient glucose consumption and catabolism is critica for survivall, and glycolysis in combination with lactate dehydrogenase is a good adaptation.

Dear Dr. Helenius, thanks for interesting question. However, any discussions regarding the effects Crabtry and Warburg during malignization of cells assume that cells are normal and have functional mitochondria. As regards the paper by Amoroso et al., did you noticed that the cells were cultured in the presence of antibiotics penicillin and streptomycin? Streptomycin is mitotoxic, therefore in grown in its presence there is no mitochondrial respiration with any substrate. Thus, in these cells it is impossible to discuss theWarburg or Crabtry effects.

I have discussed this issue in details in my Book "Practical Mitochondriology. The pitfalls and problems in studies of mitochondria" at Amazon.com. See also my recent paper in PLOS ONE "Bioenergetic and antiapoptotic properties of mitochondria from cultured prostate cancer cells...".

It has been really interesting and educative to follow this conversation. I have learnt many new aspects to my question, thank you.

I have read that glucose deprivation changes the response to hypoxia but does it really initiate some sort of hypoxic response, other than the mentioned aerobic glycolysis?

Thanks Elahu for the review recommendations I have now read only the historical review about Warburg, which was really good. This taught me that cancer cells form 70% of their ATP though aerobic glycolysis and 30% thourg TCA cycle and together their ATP production is 10% more efficient than regular cells. This is accomplished without increase in oxygen demand but with increased demand for glucose.

Augustin, your answer really helped me to understand the benefits of aerobic glycolysis to cancer cells. Lactate inhibits non cancer cell growth, loosens ECM and can be used for lipid biosynthesis.

Initially cells could go to aerobic glycolysis because of damaged mitochondrio (D´Agostino) or because TCA cycle is fed from glutaminolysis (Lagunoff). Even though I thought that the cells use glucose always as a primary energy source and would not “waist” it even if there would be a low availability.

Silanikove, you are of course right it is totally different aspect to study glucose deprivation in organism level with all hormonal responses than in cellular level. It is true that whether it is a question about, nutrients, oxygen or temperature the body will focus to keep to vital functions and organs intact. My specific interest to my original question is to study endothelial dysfunction during pathological vascular remodeling. These cells have been shown to acquire cancer cell-like phenotype; increased aerobic glycolysis, apoptosis resistant, hyper proliferative, genomic instabilities, and defects in mitochondria. We are currently studying possible explanations to this metabolic switch. So it is unlikely that it would be programed response, which is relevant on the whole organism metabolism, but this is important point to consider.

Panov, We also use P/S antibiotics in our cell culturing so routinely that didn´t pay it any attention. Thank you for this comment! I definitely have to take it in to account when planning experiments. I will see the details from your paper.

Oxygen consumption is not always linked to coupled OxPhos.The Crabtree effect will suppress respiration in cultured cells. This is an in vitro artifact. It is difficult to distinguish a Crabtree effect (glucose-suppressed respiration from the in vitro environment) from a Warburg effect (insufficient respiration from any number of intrinsic defects in mitochondrial structure or function).

Few people in the metabolism field address these issues. This is explained in detail in the book "Cancer as a Metabolic Disease"by Thomas Seyfried.

In addition to cancer, there's some nice recent papers by Dr. Luke O'Neil (Trinity College Dublin, Ireland) that demonstrates the importance of the Warburg effect during an immune challenge.

http://www.ncbi.nlm.nih.gov/pubmed/22430788

Further, we have suggested a role for the Warburg effect during environmental induced heat stress.

http://www.annualreviews.org/doi/abs/10.1146/annurev-animal-031412-103644?prevSearch=&searchHistoryKey=

Thanks Lance!

Thanks to all previus answersl. In muscle cells, the deprivation of glucose induce glycogenolysis and lactate production , which in turn promotes liver glucose production

Regina is right on track in relation to muscle cells but not malignant cells.

Oxygen will reduce anaerobic glycolysis and lactic acid production in most normal cells (Pasteur effect).Genomic mutability and essentially all hallmarks of cancer, including the Warburg effect, can be linked to impaired respiration and energy metabolism.In brief, damage to cellular respiration precedes and underlies the genome instability that accompanies tumor development. Once established, genome instability contributes to further respiratory impairment, genome mutability, and tumor progression.

http://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-century-view/

This is a great discussion topic! It is a fact that most cultured cells (both cancer and non-cancer cell types) grown in glucose-containing medium are predominantly reliant on glycolysis to meet their energy needs (Crabtree effect). One reason for this could be that although glycolysis is less efficient at generating ATP when compared to mitochondrial OXPHOS, proliferative cells prefer glycolysis because in addition to ATP it also provides most of the building blocks required for cell proliferation.

Here is a paper showing that when glucose is no longer available cells switch from glycolysis to OXPHOS, resulting in the cessation of cell proliferation.

Article Circumventing the Crabtree Effect: A method to induce lactat...

The cancer cell in constantly division requires all the glucose near and more, for that glucose is less around and it employes all other kind of systems to obtein Energy.

This may be stupid but my view is that cancer cells are cells that have stopped being just a tissue of a higher organism and started to behave as independent organisms of their own. From such perspective, their physiological adaptations could possibly be understood in evolutionary terms, like we do for parasites invading a host. Firstly, they need to proliferate and perpetuate themselves for that is the essence of life. Next, they need to become insensitive to regulatory signals from the host organism (including apoptosis and energy metabolism regulation). Finally, they need to find strategies to workaround the host organism defences (be it the immune system or chemotherapy, for instance). Tumorous cells that are successful at doing all that survive and eventually become noticed. The rest just die unnoticed.

I think that the Seyfried review already mentioned here as well as others provide several hints on how aerobic glycolysis is crucial to enable tumours achieving all their goals. One aspect that has been maybe overlooked is the fact that the tumour micro-environment (poor in glucose and oxygen) makes the immune cells dysfunctional.  

Just 2 cents from my profound ignorance on the subject.

Cheers,

Miro