January 30, 2021 // -- Scientists from the Memorial Sloan Kettering Cancer Center and others have solved a 100-year-old mystery about cancer in a recent study published in the international journal Science entitled "Glycolysis fuels phosphonositide 3-kinase signaling to Bolster T cell immunity". On the 100th anniversary of a basic discovery taught in each biochemistry textbook, in 1921, German doctor Otto Warburg observed that cancer cells were able to extract energy from glucose in an extremely inefficient way, rather than burning it with oxygen, which "fermented" like yeast to get energy, a process that occurs quickly, but most of the energy in glucose is not used. For more than
years, scientists have come up with a variety of hypoththions about the Warburg effect, including the idea that the mitochondrials of cancer cells are defective and therefore not capable of controlled burning of glucose, but none of these explanations have stood the test of time, such as that the mitochondrials of cancer cells actually work.
the study, researchers conducted a large-scale genetic and bio-chemical experiment to come up with a new answer; in fact, it boils down to a previously unsalted link between Wahlberg metabolism and the activity of a powerful enzyme in cells called PI3 kinases.
researcher Li says PI3 kinases are key signaling molecules that function almost like the general command of cell metabolism, and that most energy-consuming events in cells, including cell division, occur only when pi3 kinases give a hint.
when cells turn to Waberg metabolism, PI3 kinase activity increases, and in turn, the cell's commitment to division increases, which is a bit like giving the commander-in-chief a megaphone.
The findings in this paper correct the widely accepted view among biochemists that metabolism is a secondary factor in cell signaling, targeting metabolism or acting as an effective way to inhibit cancer growth.
Photo Source: NiH Challenge Textbook Perspectives The researchers studied the Wallberg metabolic effects in immune cells, which also rely on this seemingly inefficient metabolic pattern, and when immune cells are prompted to become infected, the type of characteristic cells called T cells changes from a typical oxygen-burning metabolic form to Wahlberg metabolism because of the increasing number and the increased number of machines fighting infection.
The key switch to control this transition is an enzyme called lactic acid dehydrogenase A (LDHA), which is produced only by the PY3 kinase signal, because of which glucose is still only partially broken down and ATP in cells is produced quickly;
study of mice by researchers found that T cells missing LDHA did not maintain the activity of PI3 kinases and were not effective against infection, which may mean that the metabolic enzymes were able to control the signal activity of cells. 'We hypothesize that metabolism is a secondary factor in growth factor signaling, in other words, growth factor signaling drives metabolism, which supports cell growth and proliferation, so if metabolic enzymes such as LDHA can affect growth factor signals through PI3 kinases, it should probably be noticed by scientists,' said li, a
Like other kinases, PI3 kinases rely on ATP to function, and since ATP is a net product of Wahlberg's metabolism, it establishes a positive feedback loop with PI3 kinase activity and ensures the continued activity of PI3 kinases, thereby ensuring cell division.
As to why activated immune cells prioritize this metabolic model, the researchers speculate that this may be related to the need for cells to produce ATP quickly to speed up cell classification and anti-infection machines; positive feedback cycles ensure that the procedure continues once activated until the infection is eliminated.
Cancer Association Although researchers have found some differences with cancer in immune cells, PI3 kinase is a key enzyme in the context of cancer that sends growth signals for cancer cells to divide and is one of the signaling paths for overactive cancer.
like immune cells, cancer cells may use Wahlberg metabolism as a way to maintain the activity of this signaling path, thus ensuring the continued growth and division of cancer cells.
same time, the findings suggest that researchers may be able to stop cancer growth by blocking the activity of waberg switch LDHA.
() References: 1: Ke Xu, Na Yin, Min Peng, et al. Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity, Science (2021). DOI：10.1126/science.abb2683【2】Scientists solve a 100-year-old mystery about cancerby Memorial Sloan Kettering Cancer Center