Tumor metabolome
Although the link between the cancer and metabolism was observed in the early days of cancer research by Otto Heinrich Warburg,[3] which is also known as Warburg hypothesis, not much substantial research was carried out until the late 1990s because of the lack of in vitro tumor models and the difficulty in creating environments that lack oxygen.
Recent research has revealed that metabolic reprogramming occurs as a consequence of mutations in cancer genes and alterations in cellular signaling.
The conversion of glucose to lactate rather than metabolizing it in the mitochondria through oxidative phosphorylation, (which can also occur in hypoxic normal cells) persists in malignant tumor despite the presence of oxygen.
This shift therefore demands that tumor cells implement an abnormally high rate of glucose uptake to meet their increased needs.
[5] As neoplastic cells accumulate in three-dimensional multicellular masses, local low nutrient and oxygen levels trigger the growth of new blood vessels into the neoplasm.
AKT1 stimulates glycolysis by increasing the expression and membrane translocation of glucose transporters and by phosphorylating key glycolytic enzymes, such as hexokinase and phosphofructokinase 2.
It provides resistance to oxidative stress that would regulates a set of genes that increase glucose metabolism and reduce mitochondrial respiration.
These mutations cause a disruption of the TCA cycle with the accumulation of fumarate or succinate, both of which can inhibit dioxygenases or prolyl hydrolases that mediate the degradation of HIF proteins.
NADPH functions as a cofactor and provides reducing power in many enzymatic reactions that are crucial for macromolecular biosynthesis.
Although aerobic glycolysis is the best documented metabolic phenotype of tumor cells, it is not a universal feature of all human cancers.
The carnitine palmitoyltransferase enzymes that regulate the β-oxidation of fatty acids may have a key role in determining some of these phenotypes.
A convergence between phenotypic and metabolic state transitions that confers a survival advantage to cancer cells against clinically used drug combinations like taxanes and anthracyclines have also been reported while drug resistant cancer cells had increased activity of both the glycolytic and oxidative pathways and glucose flux through the pentose phosphate pathway (PPP).
[21] NADPH plays an important role as an antioxidant by decreasing the reactive oxygen produced during rapid cell proliferation.
In preclinical studies, drugs such as 6-amino-nicotinamide (6-AN), which inhibits G6P dehydrogenase, the enzyme that initiates the PPP have shown anti-tumorigenic effects in leukemia, glioblastoma and lung cancer cell lines.
[9] Metabolites such as Alanine, Saturated lipids, Glycine, Lactate, Myo-Inositol, Nucleotides, Polyunsaturated fatty acids and Taurine are considered as the potential biomarkers in various studies.
