METABOLIC SOURCE OF CANCER: Amino Acid and Glucose Fermentation Maintain Energy in Mouse and Human Malignant Glioma Cells

The cancer cells have been signaling to us for decades that they're fermenting. Cut off their two fermentable fuels - glucose and glutamine - and the cancer cells will die. (Full clip: https://t.co/BkInOltfP3) Link to our recent paper: https://t.co/pSz3yz2Rt3 pic.twitter.com/YhJPFnIZK9

— Thomas N. Seyfried (@tnseyfried) January 4, 2025

 

 Here is their paper, "Amino Acid and Glucose Fermentation Maintain ATP Content in Mouse and Human Malignant Glioma Cells," Lee, D. C., Ta, L., Mukherjee, P., Duraj, T., Domin, M., Greenwood, B., … Seyfried, T. N. (2024). ASN Neuro, 16(1). https://doi.org/10.1080/17590914.2024.2422268

from Seyfried's presentation above: 

00:12. Amino acid fermentation can also participate in the dysregulated growth of the tumor cell and the amino acid that we're speaking predominantly about is glutamine and we tested all the other Amino acids. All 20 amino acids we interrogated, the cancer cells both mouse and human glioblastoma cells.  We interrogated them to ask what fuels could they use to maintain their growth?  Then we do this is very simple we just take the tumor cells and we grow them in Saline salt solution and, of course, there's no food there's nothing for them to eat and then you take and time them to see how fast they die with no food and mouse cells because they have a very high basil metabolic rate seven times faster than that of the human they die quick when you take away their fuels Mouse cells will die in 24 hours human cells human cells will die in about 72 hours, 48 to 72 hours with no fuel in what we call a buffered sailing solution.  And then what we do, we simply add individual amino acids back in and we see whether or not the viability of the cells is improved, and what we see is we do this both in the presence and absence of glucose.  Glucose alone will keep the cells alive longer but then they die because they don't have any nitrogen source.  And then we do it without glucose.  So we just do in pure nothing and then we add glucose and then we add individual amino acids back, and what we see is when we at amino acid glutamine these cells explode in growth capacity relative to all other amino acids.  Now we found a little bit of stimulation from glutamate because it's the first product that glutamine is metabolized to, but it's not nearly as powerful as glutamine.  None of the other amino acids had any come close to how powerful glutamine is so the question is when you have glucose and glutamine the two pathways are synergistic and provide all of the metabolites and all of the energy needed for rapid dysregulated growth.  So the question is how is glutamine able to facilitate the growth of the tumor is it respired through the respiration it's called and aplorotic respiratory process where the carbons glutamine entered into the TCA cycle to produce reducing equivalents allowing oxidative phosphorylation to operate producing energy or is the glutamine fermented which is generating energy through mitochondrial substrate level phosphorylation in the sucks you will call a ligase step Within the Krebs cycle or the TCA cycle so what we did and why we this paper is so important is we were able to test this hypothesis this is many different ways so many different ways so we would take all of the glucose away from the tumor in the presence of oxygen and then give glutamine with oxygen and glutamine in the absence of glucose but then that doesn't tell us whether the glutamine is fermented or has respired so we repeatedly experiment this time removing all the oxygen we grew them in a deep hypoxia in the acid of glucose and we still got ATP production in these cells yes it was significantly reduced but it was still being produced ATP was still being produced in the cancer cells in the absence of oxygen and in the absence of glucose and in the absence of glucose so the question is where is that ATP coming from so we think it's coming from the substrate level phosphorylation in the T c a cycle and we were able to show that when we use labeled glutamate glutamine C-13 glutamine we were able to see C-13 succinic acid as a waste product, that's the end product of the glutaminolysis pathway.