To promote their fast multiplication and expansion across the body, cancer cells change their metabolism. Cancer cells prefer to utilize aldohexose for aerobic metabolism rather than delivering it through the organic process glycolysis pathway. Glycolysis produces ATP and pyruvate from glucose. The ribose 5-phosphate and NADPH are then generated in the mitochondria or incorporated into the tricarboxylic acid cycle through the pentose phosphate pathway.
The Warburg Effect
The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically, even under normoxia, which contributes to chemoresistance. As a result of this, cancer cells prefer aerobic glycolysis to glucose intake. Even in the presence of oxygen and completely functional mitochondria, cancer cells’ glucose absorption and lactate generation were drastically increased. This well-known metabolic shift supplies cancer cells with the required substrates for proliferation and division, both of which are required for the growth of cancer cells and metastasis.
Otto Warburg, a Nobel laureate and a biochemist, wrote the most significant book ever written on mitochondrial malfunction and its role in cancer. Otto Warburg unwaveringly hypothesized that neoplastic transformation originated because of irreversible damage to mitochondrial respiration based on his series of experiments on cancer cell respiration and metabolism, as well as his in-depth analysis of reported works from other investigators at the time, using an approach similar to what Watson and Crick used in deciphering the DNA double-helical structure. As a result, cancer cells must depend on an inefficient glycolytic ATP production (2 ATPs glucose) rather than respiration, which produces far more ATP glucose (approximately 36 ATPs glucose). When oxygen tension is normal, Warburg claims, normal cells generate the bulk of their energy through mitochondrial respiration. The cytosol provided more than half of the energy to cancer cells, with the mitochondrial respiratory chain providing the rest. The bio energetically inefficient glycolytic dependence on which cancer cells rely for most of their energy generation is not due to a lack of oxygen; it functions even when there is enough. To meet their energy demands, cancer cells must convert to a greater glucose import mode since glycolysis is bio energetically inferior.
Glucose Metabolism and Cancer Cells
Since cancer cells thrive on expansion, aerobic glycolysis permits them to satisfy their ATP and biosynthetic precursor requirements. The purpose of aerobic glycolysis, rather than creating lactate and ATP, is to maintain a high number of glycolytic intermediates in the cells to facilitate anabolic activity. Therefore, it might explain why cancer cells consume more glucose when they are developing.
Environmental growth constraints have little effect on cancer cells. This is done by obtaining the ability to proliferate in the absence of growth signals due to mutations in receptor-associated signaling molecules, as well as being resistant to antigrowth stimuli, such as those mediated through cell-to-cell contacts. Cancer cells are pushed away from blood arteries and, as a result, from oxygen and nourishment supply in the early stages of carcinogenesis by uncontrolled cell growth. The only way for oxygen and glucose to reach the core cells of a non-vascularized tumor is by diffusion through the basement membrane and the peripheral tumor-cell layers.
CSCs (cancer-stem cells) and non-CSCs make up most cancer cells. CSCs are capable of self-renewing and causing cancer. The metabolic plasticity to which CSCs adapt is influenced by the tumor microenvironment. Instead of depending on mitochondrial infrastructure and function, CSCs choose glycolysis and the PPP. The energy produced by glycolytic metabolism allows CSCs to meet their fundamental demands. With the rising energy demands of specialized progenitor cells, the metabolic network grows.
Application of Glucose Metabolism in Treating Cancer Cells
It aids in the treatment of drug resistance and improves the efficacy of current combo therapies. Targeting glucose metabolism in therapy appears insignificant as compared to diagnosis owing to effectiveness or safety concerns. Several medications have proven effectiveness and several targets, as well as some older non-chemotherapeutic treatments with novel elements of tumor glucose metabolism.
Modulating specific targets with altered glycolytic metabolism would lessen therapeutic toxicity when compared to standard cytotoxic treatments. Several investigations have found that combining therapy with vitamin C reduces ATP and NADPH generation by interfering with glycolysis and the TCA cycle. It can destroy cancer cells by raising oxidative stress and inhibiting cancer cell survival and invasion further.
Cancer cells in hypoxic environments have been identified as important and promising targets for cancer therapy because they influence tumor malignancy and resistance to traditional therapies, and they are only found in malignant tumors, not normal tissues. Despite the substantial research on cancer metabolism that has yielded exciting discoveries over the previous few decades, uncertainties remain. Nonetheless, technological advancements are likely to unearth a slew of new features of glucose metabolism in cancer that may be used to improve patient treatment.