Aqsa Khan, Jamia Millia Islamia
The History Behind The Warburg Effect
In the 1920s, Otto Warburg described the increased production of lactate utilizing glucose even in an adequate supply of oxygen in tumor cells. Warburg, from his study, concluded that this impairment in cancer cells is due to dysfunctional mitochondria.
Over a period, however, with the advent of technology, scientists began to study the conclusive role of mitochondria in cancer. Contrary to Warburg’s theory, scientists discovered that mitochondria were completely functional in cancer cells. In the 1950s, Chance and colleagues first questioned Warburg’s findings, indicating through their studies intact and functioning cytochromes in most tumor cells dismissing claims of mitochondrial malfunction.
Furthermore, Weinhouse (1956), Aisenberg (1961), Vaupel (1974) and Shapot (1976) and several additional researchers presented considerable evidence that oxidative phosphorylation (OXPHOS) and a normal Krebs cycle (TCA cycle) persist in the great majority in almost all tumors excluding the malignant tumors, indicating that most malignancies display the Warburg effect while maintaining mitochondrial respiration. In the 1970s, Efraim Racker coined the term ‘Warburg Effect’ Furthermore, several studies also demonstrated that Warburg’s theory does not apply to all tumors, as several cell lines were found to have mitochondrial activity. Even after 100 years of research, the benefits of Warburg’s theory in tumor development have been a source of dispute.
In normal cells, glucose is converted to pyruvate, which is then fully oxidized to CO2 in the mitochondria via the TCA cycle and oxidative phosphorylation (OXPHOS). If there is limited availability of O2 only then, pyruvate is metabolized to lactate. Whereas in cancer cells, the rate of glucose uptake is dramatically enhanced, and lactate is produced even in the presence of sufficient oxygen supply; this has been described as the Warburg effect (aerobic glycolysis). To fulfill the high cellular energy requirement, cancer cells require energy and food replenishment. Despite the functional oxidative phosphorylation pathway, growing cancer cells resort to aerobic glycolysis to maintain cellular energy balance. When compared to normal cells, cancer cells’ metabolic profiles are reprogrammed, and these metabolic abnormalities contribute to the maintenance and survival of malignant cells. The Warburg effect has been found in tumors such as breast, colorectal, lung, and glioblastoma. Recent cancer biochemistry and biology findings have helped to clarify the pathogenesis of the Warburg effect and its involvement in tumor development. Some of the significant proposals are discussed below.
Rapid ATP Production
During adequate oxygen supply in normal cells, the oxidation of 1 mole of glucose to CO2 and H2O generates about 38 ATPs, i.e., 2 ATP in glycolysis, 2 ATP in TCA cycle, and 34 ATP in the electron transport chain and oxidative phosphorylation.
Whereas in cancer cells, even in the presence of adequate oxygen supply, aerobic glycolysis is performed where 1 mole of glucose is converted to pyruvate yielding 2 ATPs. However, aerobic glycolysis is approximately 100 times faster, allowing it to supply significantly more ATP per unit time than oxidative glucose metabolism. In reality, as long as enough glucose is accessible from the extracellular compartment, the quantity of ATP produced over a given period is equivalent when either route of glucose metabolism is used.
Biosynthesis of Macromolecules
The Warburg effect has been postulated as an adaptive mechanism to sustain metabolic requirements during uncontrolled proliferation. Increased glucose intake is employed as a carbon source for anabolic activities that support cell growth. This extra carbon is utilized by the various branching routes that emerge from glycolysis, where it is utilized in the synthesis of proteins, lipids, and nucleic acids. Furthermore, proliferating cells have a more significant requirement for reducing equivalent, i.e., NADPH. Increased glycolysis allows the elevated synthesis of reducing equivalents via the pentose phosphate pathway, further utilized in de novo lipid synthesis.
Studies have revealed that mTOR signaling upregulates enzymes and transporters involved in glycolysis. For instance, GLUT1 (Glucose transporter 1) expression has been reported to be increased in malignancies such as lung, breast, and pancreatic cancer. A study on human glioblastoma demonstrated increased expression of hexokinase 2 (HK2) encouraged tumor development via regulating aerobic glycolysis. The study suggested HK2 as a critical mediator of the Warburg effect.
Tumor Microenvironment
The significance of lactate and acidosis in carcinogenesis, as well as lactate’s status as an oncometabolite, has gotten a lot of attention in recent years. Glutaminolysis is among the significant generators of lactate and protons in the tumor microenvironment (TME), along with the Warburg effect.
Glutaminolysis is a catabolic process that utilizes glutamine to generate ATP and lactate, among other metabolites, to fuel TCA. Lactate concentrations in blood and healthy tissue are 1.5–3 mM, while lactate released by tumor cells can reach up to 40 mM. Hypoxia causes alterations in cellular metabolic pathways, such as a higher reliance on aerobic glycolysis, which increases lactate generation when accompanied by glutaminolysis.
The local pH in the TME generally varies from 5.6 to 7.0, which facilitates tumor immune escape. High lactate generation in a poorly perfused environment causes tumor acidification. The presence of pH 6–6.5 in the tumor microenvironment is linked to metastasis, angiogenesis, and treatment resistance, a hallmark of more aggressive cancers.
Redox Homeostasis
The radical and non-radical oxygen species produced by partial reduction of oxygen are known as reactive oxygen species (ROS). Examples include superoxide anion (O2), hydrogen peroxide (H2O2), and hydroxyl radical (HO•). Subcellular organelles including mitochondria, peroxisomes, and cytochrome P-450 generate endogenous ROS as a byproduct.
Oxidative stress arises when ROS overload the cellular antioxidant defense system, whether through an increase in ROS production or a loss in cellular antioxidant capacity. Oxidative stress causes direct or indirect ROS-mediated damage to nucleic acids, proteins, and lipids and has been linked to cancer development. One of the most prominent features of cancer is the buildup of reactive oxygen species in large quantities.
ROS has a beneficial impact at low concentrations through regulating intracellular signaling by activating PTEN and tyrosine phosphatases and homeostasis; but, at high concentrations, ROS plays a significant role in protein, lipid, and DNA damage. Moreover, activation of oncogenes, stimulation of the PI3K signaling pathway, and hypoxia (low oxygen levels) all cause an increase in ROS and NOX production in cancer cells.
The Warburg effect supports cancer cell proliferation by providing reducing equivalents. The oxidative branch of the pentose phosphate pathway generates 2NADPHs per mole of glucose, preserving the antioxidative potency of GSH (glutathione) and boosting resistance in cancer cells. It can also serve as a directly acting antioxidant in the mitochondrial compartment.
Conclusion
In summary, numerous advances in the field of oncology have been accomplished in the previous decade. Never have we had such a thorough grasp of cancer cells’ metabolic and energy requirements. Researchers have discovered that this metabolic rewiring is required not just for energy production and biomass creation but also for other cancer characteristics, including migration, invasion, metastasis, and angiogenesis.
The Warburg effect and its operations in cancer cells have been studied extensively, and we now have a better knowledge of the reasons and needs for tumor cell growth. However, it has left us with an unexpected lack of understanding of its ontology.
If therapeutic breakthroughs in treating and preventing cancer using dietary and pharmaceutical intervention in metabolism, as well as utilizing glucose metabolism to regulate the immune system, is to be made, a greater knowledge of the biology of the Warburg effect is likely to be required.
Prospects for future research on the Warburg effect
- What role exactly does the Warburg effect play in cancer promotion?
- Do the prerequisites of the Warburg effect reveal anything about its function?
- How can experimental setups be designed to verify the proposed functions of the Warburg effect comprehensively?
- Does the activity of the Warburg effect shed light on its involvement in tumor evolution?
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References
- Vaupel, P., & Multhoff, G. (2021). Revisiting the Warburg effect: historical dogma versus current understanding. In Journal of Physiology (Vol. 599, Issue 6, pp. 1745–1757). J Physiol. https://doi.org/10.1113/JP278810
- Liberti, M. V., & Locasale, J. W. (2016). The Warburg Effect: How Does it Benefit Cancer Cells? In Trends in Biochemical Sciences (Vol. 41, Issue 3, pp. 211–218). Trends Biochem Sci. https://doi.org/10.1016/j.tibs.2015.12.001
- Pérez-Tomás, R., & Pérez-Guillén, I. (2020). Lactate in the tumor microenvironment: An essential molecule in cancer progression and treatment. In Cancers (Vol. 12, Issue 11, pp. 1–29). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/cancers12113244
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