Targeting Energy Metabolism in Tumour Cell

        Cancer cells rapidly metabolise glucose solely into lactic acid during the Warburg effect, creating ATP without oxidative phosphorylation. As a result, NADPH and ATP levels, which are required for the anabolic process, fall. Normally, cells create NADPH via the Krebs cycle with the input of acetyl-CoA. However, because glucose is converted to pyruvate and then to lactic acid, no acetyl-CoA is produced via the link reaction. The FAO pathway provides acetyl-CoA and NADPH to cancer cells. As a result, the FAO pathway becomes critical for cancer cell survival. Cancer treatment/remedy might be developed by targeting the FAO pathway or cancer metabolism.

      Despite the availability of plenty of oxygen, there is a remarkable increase in glycolysis and a reduction in oxidative phosphorylation of glucose in tumour cells. The "Warburg Effect" refers to this peculiar aerobic glycolysis. It is a characteristic of a rapidly developing cell or an embryonic cell that has become trapped in a tumour cell. These tumour cells profit from aerobic glycolysis in generating several cellular components that are required constantly, owing to tumour cell expansion. The Warburg effect occurred as a result of gene mutation and epigenetic changes in malignant cells, and metabolism changed further toward anabolism.

       Increased glucose absorption and reduced oxidative phosphorylation of glucose aid in the formation of precursors for ribose sugar biosynthesis, protein glycosylation, and serine synthesis, which are all precursors of macromolecule synthesis necessary for recurrent cell division. Glutamine metabolism increased, resulting in the formation of NADPH for lipid synthesis. Lactic acid begins to accumulate in the cytoplasm of tumour cells when aerobic glycolysis increases. This causes a reduction in pH and the activation of reactive oxygen species (ROS), which induces growth-promoting genes like c-myc and Ras. Increased myc and Ras expression promote nucleic acid and lipid production as well.

        Higher growth necessitates the use of additional precursors for the synthesis of biological components, such as fatty acid production. Simple fatty acid components of lipids are synthesised in a variety of methods, including hydrolysis of triglycerides by N (neutral) hydrolases in the cytoplasm or lipophagy by A (acid) hydrolases. The production of fatty acids begins with malonyl-CoA, which is then converted into various fatty acids by elongating its carbon chain, which is controlled by the enzyme fatty acid synthase. The opposing stage of fatty acid production is beta-oxidation, which breaks down fatty acids to produce NADH, FADH2, and acetyl-CoA per cycle. These processes are repeated until the 4C fatty acid is broken down into two acetyl-CoA molecules. NADH and FADH2 enter the electron transport pathways to produce ATP.

      In energy-demanding tissues such as the brain, heart, and skeletal muscle, the beta-oxidation pathway is activated. Loss of attachment (LOA) of cells to the ECM inhibits fatty acid oxidation (FAO) and catabolism, resulting in reduced pH and activated ROS. Because the only energy source remaining in the tumour cell is glucose, it increases glucose absorption and glycolysis. Various antioxidants combat ROS while also promoting the FAO pathway. LOA of tumour cells from ECM may impede glucose absorption, resulting in reduced ATP and NADPH generation and increased ROS production. LOA control by the PML (Promyelocytic Leukaemia) protein, which is regulated by PPARs (Peroxisome Proliferator-Activated Receptors), stimulates FAO activity, which aids in cell survival.

   According to Tak W Mak et al, CPT1C is an isoform of CPT1 (Carnitine PalmitoylTransferase 1) expressed in tumour cells (usually expressed in the brain) and promotes beta-oxidation, tumour development, ATP synthesis, metabolic stress tolerance, and resistance to mTORC1 inhibitors. FAO is also in charge of mitochondrial permeability transition hole creation mediated by BAK and BAX, as well as cell survival (Michael Andreeff et al). CPT1 has an apoptotic function, which monitors the action of pro-apoptotic BH3 family proteins, and both play a role in leukaemia cell survival. CPT1 is implicated in FAO, having anti-apoptotic activity, beta-oxidation reducing lipid toxicity in cells by oxidising excess lipid produced, and over-expression of ATP synthesis in leukaemia cells might all help to explain FAO's role in leukaemia cell survival.

       UCP (Uncoupling Protein) reduces ATP synthesis in response to these alterations. UCP1, UCP2, and UCP3 are involved in protonated fatty acid insertion into the matrix, insulin secretion, and fatty acid synthesis, respectively. Nika Danial et al demonstrated diffuse large B cell leukaemia (DLBCL), a kind of lymphoma that requires massive quantities of FAO for ATP synthesis and is heavily reliant on beta-oxidation for life. FAO, which is controlled by PML and PPAR, also has a function in the maintenance and survival of hematopoietic stem cells (HSCs) and leukaemia-initiating cells (LIK). FAO-initiated metabolic reprogramming boosts NADPH production when two acetyl-CoA molecules (FAO's final product) mix with oxaloacetate in the Krebs cycle, resulting in a chain reaction that produces NADPH molecules.

      NADPH is required for cancer cell maintenance since it is a coenzyme for several anabolic activities and aids in the prevention of oxidative stress. Inhibiting FAO in glioma cells causes a reduction in NADPH, which leads to ROS generation and cell death. To maintain NADPH levels, LKBI-AMPK controls both the anabolic FAS process (negatively) and the catabolic FAO process (positively via CPT1C). It also promotes FAO, which becomes a survival factor for HSCs and leukaemia cells via indirect ROS generation (by CPT1C) and direct acetyl-CoA carboxylase (ACC).