In 1921, the German physician Otto Warburg observed that cancer cells store energy from glucose in a strangely inefficient way: instead of oxidizing it {with oxygen} the cancer cells ferment it. This oxygen-independent process is fast but leaves much of the glucose untapped. Cancer cells have been shown to have defective mitochondria and therefore cannot perform controlled glucose burning. Now a research team at the Sloan Kettering Institute is coming to a previously unappreciated link between Warburg metabolism and the activity of an enzyme called PI3 kinase. PI3 kinase is a key signaling molecule that acts almost as the leader of cell metabolism, and most energy-intensive cellular events (eg division) occur only when PI3 kinase signals.
As cells shift into Warburg metabolism, PI3 kinase activity increases and in turn enhances cell commitment to division. The findings revise the commonly accepted view of biochemists who view metabolism as secondary to cellular signaling. Metabolism is an effective way to prevent the development of cancer. The metabolism of Warburg in cells of the immune system, which is also based on this seemingly inefficient form of metabolism, was studied. When immune cells are alerted to the presence of an infection, T cells shift from the typical form of metabolism υση oxygen} to Warburg metabolism as they grow in number and increase their action to fight infections.
The key switch that controls this shift is the enzyme Lactic A Dehydrogenase A (LDHA) in response to PI3 kinase signaling. As a result of this switch, glucose remains only partially distributed and ATP is rapidly produced in the cell cytosol. In contrast, when cells use oxygen to burn glucose, the partially cleaved molecules travel to the mitochondria and break down further there to delay ATP. In T-cell mice without LDHA, it was not possible to maintain PI3 kinase activity resulting in inability to effectively fight infections, indicating that this metabolic enzyme controls cell signaling activity, and cell proliferation. The metabolic enzyme LDHA affects the signaling of growth factor via PI3 kinase. Like other kinases, PI3 relies on ATP to function, and because ATP is the pure product of Warburg metabolism, it creates a feedback loop between Warburg metabolism and PI3 activity, ensuring its continued activity and cell division. Immune cells resort to this form of metabolism, believed to have to do with the need for cells to rapidly produce ATP to improve their cell division by aiming to fight infections.
PI3 kinase (a very critical kinase in cancer) sends the growth signal to divide cancer cells and is one of the most active signaling pathways in cancer. As in immune cells, cancer cells can use Warburg metabolism as a way to maintain the activity of this signaling pathway to ensure their continued growth and division. The results increase therapeutic targets for cancer development, inhibiting the activity of LDHA, the “switch” i.e. of Warburg metabolism. Regardless of oxygen availability, cancer cells typically use aerobic glycolysis to produce ATP {Warburg}, with pyruvate being diverted from the mitochondria, to which it is usually subject to oxidative phosphorylation (OXPHOS) to produce ATP. Instead, it is converted to LDHA lactate and the nicotinotide nicotinamide adenine (NAD +) is regenerated to maintain glycolysis and ATP production.
Lactic dehydrogenase A (LDHA) is a key enzyme in the aerobic glycolysis pathway, an abnormal metabolic pathway commonly seen in cancers and associated with progression and metastasis. LDHA is involved in the onset and progression of tumors, it is a critical metabolic enzyme that plays a key role in anaerobic metabolism. In a state of hypoxia, its overexpression shifts the metabolic pathway of ATP synthesis from oxidative phosphorylation to aerobic glycolysis. Hypoxia is a common phenomenon in the microenvironment of cancer cells and inhibition of LDHA is considered an excellent strategy for the treatment of cancer. Overexpression of LDHA in a cell line induced glucose uptake by increasing the Glut1 transporter, lactate secretion, MMP2, and promoting cell proliferation.
Note: Resveratrol, curcumin and epigallocatechin (EGCG) suppress LDHA. Konstantinion Research Center will attempt and measure in daily routine most of the cancer pathways for the targeted therapeutic evaluation of the cancer patients.
SOURCE: Memorial Sloan Kettering (January 21, 2021)
