🦀 What Is the Warburg Effect?

❓What Is the Warburg Effect and Why Is It a Cancer Hallmark?

• ℹ️ One of the main differences between normal healthy cells and cancer cells is that cancer cells need greater amounts of nutrients from the available bioenergy reserves.

• ℹ️ To fulfill these increased energy demands, different key metabolic pathways are activated or modified in cancer cells.

• ℹ️ These changes in metabolic pathways lead to the development of new conditions of the cell metabolism in cancer cells that differ from normal cell metabolism, such as high rate of glycolysis (glycolysis is the process in which glucose is broken down to produce energy), increased lactate production, biosynthesis of lipids, and other macromolecules (DeBerardinis et al. 2008).

• ⚠️ We just described the "Warburg effect" (Warburg 1956). So, the main characteristic of the Warburg effect is that cancer cells that are characterized by rapid proliferation consume large amounts of glucose and excrete most of the carbon as lactate instead of oxidizing it completely over pyruvate to CO2, as the normal cells do.

Dr. Otto Heinrich Warburg in the lab

⚗️ Is the Warburg Effect Aerobic or Anaerobic?

• The cornerstone of the Warburg effect is aerobic glycolysis. In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells, instead of that, rely on aerobic glycolysis, which is another name for the Warburg effect.

• ⚠️ So, yes, the Warburg Effect is aerobic

🧫 What Cells Use the Warburg Effect?

• ⚠️ Many cells, from microbes to immune cells like lymphocytes, use aerobic glycolysis (Warburg effect) during rapid proliferation.

• ⚠️ So, the Warburg effect is not exclusive to cancer cells but also normal cells use the Warburg effect to support their growth immune cells.

Do all cancers show the Warburg effect?

• ℹ️ Warburg effect is the key aspect of most cancers, and to illustrate, a positron emission tomography (PET) scan, a tool used for the diagnosis of cancer, is based on identifying the places in the body where cells are consuming extra glucose, which indicates the presence of cancer cells.

• ⚠️ However, it is important to underline that the Warburg effect is not observed in all cancer cells (Funes et al. 2007). A rough estimate is that the Warburg effect was observed in 80% of cancer cells (Hall 2018).

❓Why do cancer cells use the Warburg effect?

• ℹ️ Initially, Otto Heinrich Warburg, who described the effect and by whom it was named, proposed that tumor cells use the increase of the glycolytic flow as protection from the permanent damage of oxidative metabolism (DeBerardinis et al. 2008), (Soga 2013; DeBerardinis et al. 2008). There are some advantages for cancer cells in the increase of glucose consumption and, therefore of the Warburg effect (Soga 2013) (Kroemer and Pouyssegur 2008) (DeBerardinis et al. 2008):

  • 1️⃣ Cancer cells use glucose as the most abundant extracellular nutrient in the process of aerobic glycolysis as it actually exceeds the production of ATP in comparison to oxidative phosphorylation in situations when there is a high glycolytic flow.

  • 2️⃣ The second reason cancer cells may prefer aerobic glycolysis is that in the process of aerobic glycolysis, which is the other name of the Warburg effect, the intermediate compounds are produced that can be used for other anabolic reactions. For example, some of those intermediate products are:

    • Ribose that can be used for the synthesis of nucleotides

    • Glucose-6-phosphate to generate glycogen and ribose-5-phosphate

    • Dihydroxyacetone phosphate for the synthesis of triglycerides and phospholipids

    • Pyruvate for the synthesis of alanine and malate; and, through oxidative pentose phosphate pathway (PPP) produce nicotinamide adenine dinucleotide phosphate (NADPH).

• 3️⃣ The cancer cells produce lactic and bicarbonic acid, and lactate is the principal end product of anaerobic glycolysis. The acidic conditions create a favorable environment for the cancer cells by inhibiting the autoimmune effects of anti-cancer. In this environment, the anaerobic components (cancer cells) and aerobic (non-transformed stromal cells) are involved in metabolic pathways that act complementary by recycling products of anaerobic metabolism to maintain the survival and growth of cancer cells.

• 4️⃣ Tumors can also metabolize glucose by the pentose phosphate pathway to generate NADPH, thus ensuring antioxidant defenses against a hostile environment with chemotherapeutic agents.

• ⚠️The above described are four ways the Warburg effect enables the entire metabolism to be reorganized toward the increase of anabolic processes that further enable growth and cell proliferation in cancer cells (DeBerardinis et al. 2008; Kroemer and Pouyssegur 2008).

🥗 What is the Warburg diet?

• ℹ️ Otto Warburg, the German biochemist who, as we mentioned above, first described the Warburg effect, believed that cancers could be treated by disrupting their energy source, and one way is by diet.

• ⚠️ Near the end of his life, Otto Warburg grew obsessed with his diet and believed that most cancers were preventable. Today, what can be considered a diet based on the Warburg effect is a ketogenic diet focused on high fat, low carbohydrate intake, and adequate protein intake (Tran et al. 2020).

References

1. DeBerardinis, Ralph J., Julian J. Lum, Georgia Hatzivassiliou, and Craig B. Thompson. 2008. “The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation.” Cell Metabolism 7 (1): 11–20.

2. Funes, Juan M., Marisol Quintero, Stephen Henderson, Dolores Martinez, Uzma Qureshi, Claire Westwood, Mark O. Clements, et al. 2007. “Transformation of Human Mesenchymal Stem Cells Increases Their Dependency on Oxidative Phosphorylation for Energy Production.” Proceedings of the National Academy of Sciences of the United States of America 104 (15): 6223.

3. Hall, Christine. 2018. “Connecting the Warburg Pathway to Cancer Growth.” TMC News. October 2, 2018. https://www.tmc.edu/news/2018/10/connecting-the-warburg-pathway-to-cancer-growth/.

4. Kroemer, Guido, and Jacques Pouyssegur. 2008. “Tumor Cell Metabolism: Cancer’s Achilles' Heel.” Cancer Cell. https://doi.org/10.1016/j.ccr.2008.05.005.

5. Soga, Tomoyoshi. 2013. “Cancer Metabolism: Key Players in Metabolic Reprogramming.” Cancer Science 104 (3): 275–81.

6. Tran, Quangdon, Hyunji Lee, Chaeyeong Kim, Gyeyeong Kong, Nayoung Gong, So Hee Kwon, Jisoo Park, Seon-Hwan Kim, and Jongsun Park. 2020. “Revisiting the Warburg Effect: Diet-Based Strategies for Cancer Prevention.” BioMed Research International 2020 (August): 8105735.

7. Warburg, O. 1956. “On Respiratory Impairment in Cancer Cells.” Science 124 (3215): 269–70.